Haloalkyl ester derivatives of coumarin for the treatment of coagulation disorders

ABSTRACT

The subject invention provides anticoagulant compounds of formula I: 
                         
and pharmaceutically acceptable salts thereof, wherein R 1 , R 3 , n and Ar are as defined herein. The compounds of the subject invention can be used to treat at-risk populations thereby bringing relief of symptoms, improving the quality of life, preventing acute and long-term complications, reducing mortality and treating accompanying disorders. The invention further comprises pharmaceutical compositions comprising the compounds and salts of the invention, as well as methods of using the compounds, salts, and compositions of the invention.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.11/467,813, filed Aug. 28, 2006, now U.S. Pat. No. 7,285,671; which is acontinuation of U.S. application Ser. No. 11/101,714, filed Apr. 8,2005, now U.S. Pat. No. 7,253,208; which claims priority from U.S.Provisional Application No. 60/561,121, filed Apr. 8, 2004; and itscontinuation of U.S. application Ser. No. 10/822,129 filed Apr. 8, 2004,now U.S. Patent No. 7,145,020; all of which are incorporated herein byreference.

BACKGROUND OF INVENTION

Warfarin (coumarin) is an anticoagulant that acts by inhibiting vitaminK-dependent coagulation factors. Warfarin based compounds are,typically, derivatives of 4-hydroxycoumarin, such as3-(α-acetonylbenzyl)-4-hydroxycoumarin (COUMADIN). COUMADIN and othercoumarin anticoagulants inhibit the synthesis of vitamin K dependentclotting factors, which include Factors II, VII, IX and X. Anticoagulantproteins C and S are also inhibited by warfarin anticoagulants. Warfarinis believed to interfere with clotting factor synthesis by inhibitingvitamin K epoxide reductase, thereby inhibiting vitamin K regeneration.

An anticoagulation effect is generally seen about 24 hours afteradministration of a single dose of warfarin and is effective for 2 to 5days. While anticoagulants have no direct effect on an establishedthrombus and do not reverse ischemic tissue damage, anticoagulanttreatment is intended to prevent the extension of formed clots and/or toprevent secondary thromboembolic complications. These complications mayresult in serious and possibly fatal sequelae.

The FDA has approved warfarin for the following indications: 1) thetreatment or prophylaxis of venous thrombosis and pulmonary embolism, 2)thromboembolic complications associated with atrial fibrillation and/orcardiac valve replacement, and 3) reducing the risk of death, recurringmyocardial infarction, and stroke or systemic embolism after myocardialinfarction.

A number of adverse effects are associated with the administration ofwarfarin. These include fatal or nonfatal hemorrhage from any tissue ororgan and hemorrhagic complications such as paralysis. Other adverseeffects include paresthesia including feeling cold and chills; headache;chest, abdomen, joint, muscle or other pain; dizziness; shortness ofbreath; difficult breathing or swallowing; unexplained swelling,weakness, hypotension, or unexplained shock. Other adverse reactionsreported include hypersensitivity/allergic reactions, systemiccholesterol microembolization, purple toes syndrome, hepatitis,cholestatic hepatic injury, jaundice, elevated liver enzymes,vasculitis, edema, fever, rash, dermatitis, including bullous eruptions,urticaria, abdominal pain including cramping, flatulence/bloating,fatigue, lethargy, malaise, asthenia, nausea, vomiting, diarrhea, pain,headache, dizziness, taste perversion, pruritus, alopecia and coldintolerance.

Drug toxicity is an important consideration in the treatment of humansand animals. Toxic side effects resulting from the administration ofdrugs include a variety of conditions that range from low grade fever todeath. Drug therapy is justified only when the benefits of the treatmentprotocol outweigh the potential risks associated with the treatment. Thefactors balanced by the practitioner include the qualitative andquantitative impact of the drug to be used as well as the resultingoutcome if the drug is not provided to the individual. Other factorsconsidered include the physical condition of the patient, the diseasestage and its history of progression, and any known adverse effectsassociated with a drug.

Drug elimination is the result of metabolic activity upon the drug andthe subsequent excretion of the drug from the body. Metabolic activitycan take place within the vascular supply and/or within cellularcompartments or organs. The liver is a principal site of drugmetabolism. The metabolic process can be broken down into primary andsecondary metabolism, also called phase-1 and phase-2 metabolism. Inphase-1 metabolism, the drug is chemically altered by oxidation,reduction, hydrolysis, or any combination of the aforementionedprocesses and usually yields a more polar product than the parent drug.In Phase-2 metabolism the products of the phase-1 reaction are combinedwith endogenous substrates, e g., glucuronic acid, to yield an additionor conjugation product that is even more hydrophilic than the product ofphase-1 and which is readily eliminated in the bile or in the urine. Insome cases, a drug can undergo only phase-2 (conjugation) metabolism, inother cases a drug can be eliminated unchanged. The first step in suchsynthetic reactions is often an oxidative conjugation per-formed by thecytochrome P450 (CYP450) system. Metabolites formed in phase-2 reactionsare typically the product of a conjugation reaction performed by atransferase enzyme. These reactions include glucuronidation, amino acidconjugation, acetylation, sulfoconjugation, and methylation,

Mammalian cytochrome P450 enzymes (CYP450), including human CYP450, aremembrane-bound heme-containing proteins that were originally discoveredin rat liver microsomes. In order to function, CYP450 enzymes need asource of electrons. There are two different kinds of electron transferchains for CYP450s. These depend on the location of the enzyme in thecell. Some P450s are found in the mitochondrial inner membrane and someare found in the endoplasmic reticulum (ER). The protein that donateselectrons to CYP450s in the ER is called NADPH cytochrome P450reductase. Ferredoxin is the immediate donor of electrons to the CYP450sin mitochondria (CYP11A1, CYP11B1, CYP11B2, CYP24, CYP27A1, CYP27B1,CYP27C1). NADPH is the source of electrons that flow from ferredoxinreductase to ferredoxin and then to CYP450. A few P450s also can acceptelectrons from cytochrome b5.

Polymorphisms (differences in DNA sequence found at 1% or higher in apopulation) can lead to differences in drug metabolism, so they areimportant features of CYP450 genes in humans. CYP2C19 has a polymorphismthat changes the enzyme's ability to metabolize mephenytoin (a markerdrug). In Caucasians, the polymorphism for the poor metabolizerphenotype is only seen in 3% of the population. However, it is seen in20% of the Asian population. Because of this difference, it is importantto be aware of a person's race when drugs are given that are metabolizeddifferently by different populations. Some drugs that have a narrowrange of effective dose before they become toxic might be overdosed in apoor metabolizer.

CYP2D6 is perhaps the best studied P450 with a drug metabolismpolymorphism. This enzyme is responsible for more than 70 different drugoxidations. Since there may be no other way to clear these drugs fromthe system, poor metabolizers may be at severe risk for adverse drugreactions. CYP2D6. Substrates include antiarrhythmics (Flecainide,Mexiletine, Propafenone), antidepressants (Amitriptyline, Paroxetine,Venlafaxine, Fluoxetine, Trazadone), antipsychotics (Clorpromazine,Haloperidol, Thoridazine), beta-blockers (Labetalol, Timolol,Propanolol, Pindolol, Metoprolol), analgesics (Codeine, Fentanyl,Meperidine, Oxycodone, Propoxyphene), and many other drugs. CYP2E1 isinduced in alcoholics. There is a polymorphism associated with this genethat is more common in Chinese people.

The CYP3A subfamily is one of the most important drug metabolizingfamilies in humans CYP3A4 is “the most abundantly expressed CYP450 inhuman liver” (Arch. Biochem. Biophys. 369, 11-23 1999) CYP3A4 is knownto metabolize more than 120 different drugs, e.g., acetaminophen,codeine, cyclosporin A, diazepam, erythromycin, lidocaine, lovastatin,taxol, cisapride, terfenadine, and warfarin, to name a few.

The number of adverse drug reactions (ADRs) in the United States hasrisen dramatically in recent years and now represents a criticalnational health problem. The World Health Organization (WHO) defines anADR as “a response to a drug that is noxious and unintended and occursat doses normally used in man for the prophylaxis, diagnosis or therapyof disease, or for modification of physiological function”. To highlightthe importance of error in the genesis of ADRs and the fact that most(30-80%) ADRs are preventable, a more recent definition of an ADR is “anappreciably harmful or unpleasant reaction, resulting from anintervention related to the use of a medicinal product, which predictshazard from future administration and warrants prevention or specifictreatment, or alteration of the dosage regimen, or withdrawal of theproduct.”

Because ADRs are a major source of morbidity and mortality in our healthcare system, reducing the incidence of ADRs has become a nationalpriority (FDA, Center for Drug Evaluation and Research). According toformal estimates, greater than 2.5 million ADRs occur each year inhospitals, ambulatory settings and nursing homes, resulting in over106,000 deaths, and costing the US economy $136B annually indrug-related morbidity and mortality. This expense is greater than theannual cost of cardiovascular disease and diabetes in the United States.In addition, the estimated mortality rate associated with ADRs make themthe fourth leading cause of death in this country.

Many ADRs arise from the fact that most drugs developed by thepharmaceutical industry significantly interact with components of theCYP system, either by relying on them for their metabolism and/or byinhibiting or inducing various CYP fractions. In other words, because somany important drug classes (e.g., antihypertensives, antihistamines,antidepressants, immunosuppressants, statins) interact with the CYPsystem, it can act as a “bottleneck” for the safe metabolism andelimination of these agents and lead to toxic effects. With regard todrug metabolism, two fractions of the CYP system merit special mention:CYP3A4 and CYP2D6. Approximately one half of all known drugs interactwith CYP3A4. Likewise, CYP2D6, an enzyme fraction whose activity ishighly dependent on genetics (genetic polymorphisms), metabolizes onethird of drugs in clinical use. Both of these enzymes are involved inthe metabolism of warfarin-like compounds.

The vast majority (70-90%) of ADRs occur as extensions of their expectedpharmacological effects (exaggerated pharmacology). This is particularlyrelevant to the use of warfarin since the extension of the warfarinpharmacological effect is bleeding. Although many different factors cancontribute to the development of ADRs, altered drug metabolism leadingto elevated drug levels, either due to drug interactions at theenzymatic level, genetic alterations in enzyme activity, and/or organdysfunction (liver, kidney), play a particularly important role in thegenesis of ADRs.

Drug therapy using warfarin is particularly difficult because themetabolism of warfarin is complex and subject to interactions with ahost of other drugs, including drugs that are commonly prescribed inpatients suffering from atrial fibrillation, such as amiodarone forexample. Warfarin is a mixture of enantiomers having different intrinsicactivities at the vitamin It epoxide reductase (VKER) enzyme. Theseenantiomers have different metabolic pathways using different CYP450isozymes. The CYP450 metabolic system is highly inducible or repressibleby a host of external factors such as diet and other medications. Also,the CYP450 system is subject to many genetic variations and has a lowcapacity and is easily saturable. For these reasons the metabolism ofwarfarin is subject to unpredictable variations and each enantiomer hasa different metabolic fate and different potencies at the VKER enzyme.

In addition, warfarin activity at the VKER enzyme results in inhibitionof coagulation factors II, VII, IX, and X, which have differenthalf-lives of their own, ranging from hours (factor VII) to days (factorX). Because of this complex situation, the pharmacological effect(increased coagulation time) of warfarin becomes apparent only 5 to 10days after a dose. It is therefore easy to understand why warfarintherapy is extremely difficult to predict and why patients are at highrisk of bleeding complications including death. In the current state ofwarfarin therapy, patients on warfarin must report to a coagulation labonce a week in order to be monitored and in order to detect any earlyrisk of bleeding complications. Even with this strict monitoring system,many patients on warfarin die every year from bleeding complications.

The potential clinical problems and business risk associated withdeveloping drugs, which must past through the P450 metabolism“gauntlet”, is markedly increased in the United States by the followingtwo facts: 1) the number of prescriptions filled in this country hasincreased to about 3 billion per year or 10 per person, and 2) patients,particularly those that live longer and have more complex medicalproblems, tend to take multiple medications. The latter issue isimportant because the incidence of ADRs rises exponentially whensubjects take more than four drugs. Although it is good practice toavoid polypharmacy, in many cases this is not possible because patientsrequire different classes of drugs to effectively treat complex medicalconditions.

The landscape of drug R&D is littered by failed drugs that werewithdrawn by the FDA because they caused fatal ADRs involving CYPmetabolism. These drugs were clinically effective and in many casescommercially successful. Notable drugs that were withdrawn due toADR-related deaths involving CYP450 metabolism include terfenadine(February 1998), astemizole (July 1999) and cisapride (January 2000). Ineach of these cases, drug interactions involving CYP3A4 causedconcentrations of the pharmaceutical agent to increase to such a degreethat it significantly inhibited a particular type of potassium channelin the heart called I_(Kr), which in turn, prolonged the QT interval andcaused a potentially fatal form of ventricular tachyarrhythmia calledtorsades de pointes.

A warfarin analog that has a controllable and a predictable metabolicfate, not depending on CYP450, is therefore highly desirable and wouldbe an important addition to the armamentarium of drugs available fortreating atrial fibrillation patients. Certain warfarin analogs havebeen previously reported. See, for example, WO 02/085882, which isincorporated herein by reference.

SUMMARY OF THE INVENTION

The subject invention provides compounds and pharmaceutical compositionsthat are useful as anticoagulants or useful in anticoagulant therapy.

In a broad aspect, the invention provides compounds of formula I

or pharmaceutically acceptable salts thereof, or isomers thereof,wherein

-   R₁ is H or —(C₁-C₄ alkyl)-CO₂R₂; wherein-   R₂ is H or C₁-C₆ alkyl;-   R₃ at each occurrence is independently halogen, OH, C₁-C₆ alkyl,    C₁-C₆ alkoxy, C₁-C₄ haloalkyl, or C₁-C₄ haloalkoxy;-   n is 0, 1, 2,3, or 4,-   p is 0, 1, or 2; and-   Ar is an aryl group optionally substituted with at least one group    that is —COR₅, —(C₁-C₆ alkyl)-COR₅, —(C₀-C₆ alkyl)-O—R₆, halogen,    OH, amino, mono or dialkylamino, hydroxyalkyl, C₁-C₄ haloalkyl, or    C₁-C₄ haloalkoxy, wherein    -   R₅ is C₁-C₈ alkoxy optionally substituted with 1 or 2 groups        that are independently OH, C₁-C₄ alkoxy, heterocycloalkyl, C₃-C₇        cycloalkyl, —SO₂—(C₁-C₄ alkyl), —SO₂—(C₁-C₄ haloalkyl), or        —SO₂-phenyl, OH, amino, mono or dialkylamino, or C₁-C₆        haloalkoxy optionally substituted with 1 OH, wherein the cyclic        portions of the above are optionally substituted at a        substitutable position with groups that are independently C₁-C₄        alkyl, C₁-C₄ alkoxy, halogen, OH, C₁-C₄ haloalkyl, C₁-C₄        haloalkoxy, amino, or mono or dialkylamino;    -   and    -   R₆ is C₁-C₆ alkanoyl, aryl C₁-C₆ alkanoyl, aryl C₁-C₆ alkyl,        (C₁-C₆ alkyl)-O-aryl, or aryl, wherein the alkyl portions of the        alkanoyl groups are optionally substituted with one or more        halogens and_wherein the aryl groups are optionally substituted        at each substitutable position with a group that is C₁-C₄ alkyl,        C₁-C₄ alkoxy, halogen, OH, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy,        amino, or mono or dialkylamino.

The compounds of formula I interact with VKER and/or are useful asanticoagulants and/or in anticoagulant therapy. The invention also,encompasses pharmaceutical compositions containing the compounds ofFormula I, and methods employing such compounds or compositions in thetreatment of coagulation disorders.

The invention also provides a method of treating a patient who has acoagulation disorder or who is at risk of developing a coagulationdisorder and who is in need of such treatment which comprisesadministration of a therapeutically effective amount of a compound offormula (I).

In another aspect, the invention provides methods of preparing thecompounds of interest, as well as intermediates useful in preparing thecompounds of interest.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows VKER inhibitory activity of3-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-3-(4-trifluoromethoxy-phenyl)-propionicacid.

FIG. 2 shows VKER inhibitory activity of4-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid2,2,3,3,3-pentafluoro-propyl ester.

FIG. 3 shows VKER inhibitory activity of4-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid3,3,3-trifluoro-propyl ester.

FIG. 4 shows VKER inhibitory activity of4-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid2,2,3,3,3-pentafluoro-1-methyl-propyl ester.

FIG. 5 shows VKER inhibitory activity of4-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid 4-fluoro-benzylester.

FIG. 6 shows VKER inhibitory activity of4-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid2-(4-fluoro-phenoxy)-ethyl ester.

FIG. 7 shows VKER inhibitory activity of4-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid2,2,2-trifluoro-1-methyl-ethyl ester.

FIG. 8 shows VKER inhibitory activity of4-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid2,2,2-trifluoro-1-trifluoromethyl-ethyl ester.

FIG. 9 shows VKER inhibitory activity of4-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid2,2,2-trifluoro-1-methyl-1-trifluoromethyl-ethyl ester.

FIG. 10 shows VKER inhibitory activity of warfarin.

FIG. 11 shows VKER inhibitory activity of4-[(4-hydroxy-2-oxo-2H-chromen-3-yl)methyl]benzoic acid.

FIG. 12 shows the effect of fluorination on the metabolism by cytochromeP450 and esterase in pooled human microsomes. Peak area ratios are shownfor microsomal incubations in the presence (solid bars) or absence (openbars) of NADPH. Solid bars represent CYP450+ esterase and open barsrepresent esterase alone.

FIG. 13 shows the effect of fluorination on the metabolism by cytochromeP450 and esterase in pooled human microsomes. Peak area ratios are shownfor microsomal incubations in the presence (solid bars) or absence (openbars) of NADPH. Solid bars represent CYP450+ esterase and open barsrepresent esterase alone.

FIG. 14 shows the disappearance of a parent compound in pooled humanmicrosomes containing NADPH, in the absence (solid bars) of paraoxon, orin the presence (open bars) of paraoxon, a known esterase inhibitor.

DETAILED DISCLOSURE

In one aspect, the invention provides compounds of formula I-a, i.e.,compounds of formula I, wherein n is 0, 1, 2, or 3.

In another aspect, the invention provides compounds of formula I-b,i.e., compounds of formula I-a, wherein R₁ is H or —(C₁-C₄ alkyl)-CO₂R₂;wherein R₂ is H.

In still another aspect, the invention provides compounds of formulaI-c, i.e., compounds of formula I-b, wherein n is 1 and R₃ is halogen.

In yet another aspect, the invention provides compounds of formula I-d,i.e., compounds of formula I-b, wherein n is 0.

In still yet another aspect, the invention provides compounds of formulaI-e, i.e., compounds of either formulas I-c or I-d, wherein p is 1.

In yet still another aspect, the invention provides compounds and saltsof formula II, i.e., compounds of formula I having the formula:

wherein:

-   n is 0, 1, or 2;-   R₁ is H or CH₂COOH;-   R₃ at each occurrence is independently halogen, OH, C₁-C₆ alkyl,    C₁-C₆ alkoxy, C₁-C₄ haloalkyl, or C₁-C₄ haloalkoxy; and-   R₂₀, R₃₀, and R₄₀ are independently H, —(C₀-C₆ alkyl)-COR₅, —(C₁-C₆    alkyl)-COR₅, —(C₀-C₆ alkyl)-O—R₆, halogen, OH, amino, mono or    dialkylamino, hydroxyalkyl, C₁-C₄ haloalkyl, or C₁-C₄ haloalkoxy,    wherein    -   R₅ is C₁-C₆ alkoxy optionally substituted with 1 or 2 groups        that are independently OH, C₁-C₄ alkoxy, piperidinyl,        pyrrolidinyl, morpholinyl, piperazinyl, C₃-C₇ cycloalkyl,        —SO₂—(C₁-C₄ alkyl), —SO₂—(C₁-C₄ haloalkyl), or —SO₂-phenyl, OH,        amino, mono or dialkylamino, or C₁-C₆ haloalkoxy optionally        substituted with 1 OH, wherein the cyclic portions of the above        are optionally substituted at a substitutable position with        groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy,        halogen, OH, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, amino, or mono        or dialkylamino;    -   and    -   R₆ is C₁-C₆ alkanoyl, phenyl C₁-C₆ alkanoyl, (C₁-C₆        alkyl)-O-phenyl, phenyl C₁-C₆ alkyl, or phenyl, wherein the        alkyl portions of the alkanoyl groups are optionally substituted        with one or more halogens and wherein the phenyl groups are        optionally substituted with 1, 2, 3, 4, or 5 groups that are        independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, OH, C₁-C₄        haloalkyl, C₁-C₄ haloalkoxy, amino, or mono or dialkylamino

In another aspect, the invention provides compounds of formula II-a,i.e., compounds of formula II, wherein R₁ is H.

In still another aspect, the invention provides compounds of formulaII-b, i.e., compounds of formula II-a, wherein R₂₀ is —(C₀-C₆alkyl)-COR₅.

In yet another aspect, the invention provides compounds of formula II-c,i.e., compounds of formula II-b, wherein R₅ is C₁-C₆ alkoxy optionallysubstituted with 1 or 2 groups that are independently OH, C₁-C₄ alkoxy,piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl, C₃-C₇ cycloalkyl,—SO₂—(C₁-C₄ alkyl), —SO₂—(C₁-C₄ haloalkyl), or —SO₂-phenyl wherein thecyclic portions of the above are optionally substituted at asubstitutable position with groups that are independently C₁-C₄ alkyl,C₁-C₄ alkoxy, halogen, OH, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, amino, ormono or dialkylamino.

In still yet another aspect, the invention provides compounds of formulaII-d, i.e., compounds of formula II-c, wherein R₅ is C₁-C₆ alkoxyoptionally substituted with 1 group that is piperidinyl, pyrrolidinyl,morpholinyl, or piperazinyl wherein the cyclic portions of the above areoptionally substituted at a substitutable position with groups that areindependently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, OH, C₁-C₄ haloalkyl,C₁-C₄ haloalkoxy, amino, or mono or dialkylamino.

In still another aspect, the invention provides compounds of formulaII-e, i.e., compounds of formula II-c, wherein R₅ is C₁-C₆ alkoxyoptionally substituted with 1 group that is —SO₂—(C₁-C₄ alkyl),—SO₂—(C₁-C₄ haloalkyl), or —SO₂-phenyl wherein the cyclic portions ofthe above are optionally substituted at a substitutable position withgroups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, OH,C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, amino, or mono or dialkylamino,

In another aspect, the invention provides compounds of formula II-f,i.e., compounds of formula II-c, wherein R₅ is C₁-C₆ alkoxy optionallysubstituted with C₃-C₇ cycloalkyl (preferably C₃-C₆ cycloalkyl, morepreferably C₃-C₅ cycloalkyl, still more preferably, cyclopropyl) whereinthe cyclic portions of the above are optionally substituted at asubstitutable position with groups that are independently C₁-C₄ alkyl,C₁-C₄ alkoxy, halogen, OH, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, amino, ormono or dialkylamino.

In still another aspect, the invention provides compounds of formulaII-g, i.e., compounds of formula II-b, wherein R₅ is OH, amino, mono ordialkylamino, or C₁-C₆ haloalkoxy.

In yet another aspect, the invention provides compounds of formula II-h,i.e., compounds of formula II-g, wherein R₅ is amino, or mono ordi(C₁-C₆ alkyl)amino.

In yet still another aspect, the invention provides compounds of formulaII-i, i.e., compounds of formula II-b, wherein R₅ is C₁-C₆ haloalkoxyoptionally substituted with 1 OH.

In yet another aspect, the invention provides compounds of formula II-j,i.e., compounds of formula II-j, wherein R₅ is—CH₂C(halogen)₂C(halogen)₃, —CH₂CH₂C(halogen)₃, where each halogen isindependently F or Cl.

In still another aspect, the invention provides compounds of formulaII-k, i.e., compounds of formula II-aa, wherein R₅ is —CH₂CF₂CF₃,—CH₂CH₂CF₃.

In another aspect, the invention provides compounds of formula II-l,i.e., compounds of formula II-z, wherein R₅ is—CH(CH₃)C(halogen)₂C(halogen)₃, —CH(CH₂halogen)₂, —CH(CH₃)C(halogen)₃,—CH(C(halogen)₃)₂, —C(CH₃)(C(halogen)₃)₂, or —CH(OH)C(halogen)₃, whereeach halogen is independently F or Cl.

In yet another aspect, the invention provides compounds of formulaII-ll, i.e., compounds of formula II-cc, wherein R₅ is —CH(CH₃)CF₂CF₃,—CH(CH₂F)₂, —CH(CH₃)CF₃, —CH(CF₃)₂, —C(CH₃)(CF₃)₂, or —CH(OH)CF₃.

In still another aspect, the invention provides compounds of formulaII-m, i.e., compounds of formula II-l, wherein R₅ is—C(CH₃)(C(halogen)₃)₂ preferably each halogen is F.

In still yet another aspect, the invention provides compounds of formulaII-n, i.e., compounds of formula II-l, wherein R₅ is —CH(OH)C(halogen)₃.In one case, the stereogenic center in R₅ has the S-configuration. Inanother case, the stereogenic center in R₅ has the R-configuration.

In another aspect, the invention provides compounds of formula II-p,i.e., compounds according to any one of formulas II-a, II-b, II-c, II-d,II-e, II-f, II-h, II-I, II-j, II-k, II-l, II-ll, II-m, or II-n, whereinat least one of R₃₀ and R₄₀ is H.

In still yet another aspect, the invention provides compounds of formulaII-p, i.e., compounds of formula II-o, wherein one of R₃₀ and R₄₀ ishalogen (in one aspect, F or Cl), OH, amino, mono ordi(C₁-C₄)alkylamino, hydroxy(C₁-C₄)alkyl, CF₃, or OCF₃.

In yet still another aspect, the invention provides compounds of formulaII-q, i.e., compounds of formula II-gg, wherein both R₃₀ and R₄₀ are H.

In yet another aspect, the invention provides compounds of formulaII-q1, i.e., compounds according to any one of formulas II-gg, II-hh, orII-ii wherein n is 1.

In yet still another aspect, the invention provides compounds of formulaII-q2, i.e., compounds of formula II-q1, wherein R₃ is halogen, OH,C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₂ haloalkyl, or C₁-C₂ haloalkoxy.

In still yet another aspect, the invention provides compounds of formulaII-q3, i.e., compounds of formula II-q2, wherein R₃ is halogen, OH,C₁-C₄ alkyl, C₁-C₄ alkoxy, CF₃, or OCF₃.

In still another aspect, the invention provides compounds of formulaII-q4, i.e., compounds of formula II-q3, wherein R₃ is halogen.

In yet another aspect, the invention provides compounds of formulaII-q5, i.e., compounds of formula II-q3, wherein R₃ is OH, C₁-C₄ alkyl,or C₁-C₄ alkoxy.

In yet still another aspect, the invention provides compounds of formulaII-q6, i.e., compounds of formula II-q3, wherein R₃ is CF₃ or OCF₃.

In still another aspect, the invention provides compounds of formulaII-q 7, i.e., compounds according to any one of formulas II-o, II-p, orII-q wherein n is 0.

In another aspect, the invention provides compounds of formula II-q8,i.e., compound according to formula II-a, wherein R₂₀ is (C₀-C₆alkyl)-OR₆.

In yet still another aspect, the invention provides compounds of formulaII-q9, i.e., compounds of formula II-q8, wherein R₆ is C₁-C₆ alkanoyl,wherein the alkyl portion of the alkanoyl group is substituted with oneor more halogens (preferably F or Cl, more preferably, F.) Or R₆ can be—(C₁-C₄ alkyl)-phenyl, —(C₁-C₄ alkanoyl)-phenyl, or phenyl, wherein thephenyl groups are optionally substituted with 1, 2, 3, 4, or 5 groupsthat are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, OH, C₁-C₄haloalkyl (such as CF₃), C₁-C₄ haloalkoxy (such as OCF₃), amino, or monoor di C₁-C₆ alkylamino.

In still yet another aspect, the invention provides compounds of formulaII-q10, i.e., compound according to formula II-q9, wherein R₂₀ is—(C₀-C₆ alkyl)-O—R₆.

In still yet another; aspect, the invention provides compounds offormula II-q11, i.e., compound according to formula II-q10, wherein R₂₀is —(C₀-C₄ alkyl)-O—R₆.

In another aspect, the invention provides compounds of formula II-q12,i.e., compounds according to any one of formulas II-q8, II-q9, II-q10,or II-q11, wherein at least one of R₃₀ and R₄₀ is H.

In still yet another aspect, the invention provides compounds of formulaII-q13, i.e., compounds of formula II-q12, wherein one of R₃₀ and R₄₀ ishalogen (in one aspect, F or Cl), OH, amino, mono ordi(C₁-C₄)alkylamino, hydroxy(C₁-C₄)alkyl, CF₃, or OCF₃.

In yet still another aspect, the invention provides compounds of formulaII-q14, i.e., compounds of formula II-q12, wherein both R₃₀ and R₄₀ areH.

In yet another aspect, the invention provides compounds of formulaII-q15, i.e., compounds according to any one of formulas II-q8, II-q9,II-q10, II-q11, II-q12, II-q13, or II-q14 wherein n is 1.

In yet still another aspect, the invention provides compounds of formulaII-q16, i.e., compounds of formula II-q15, wherein R₃ is halogen, OH,C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₂ haloalkyl, or C₁-C₂ haloalkoxy.

In still yet another aspect, the invention provides compounds of formulaII-q17, i.e., compounds of formula II-q16, wherein R₃ is halogen, OH,C₁-C₄ alkyl, C₁-C₄ alkoxy, CF₃, or OCF₃.

In still another aspect, the invention provides compounds of formulaII-q18, i.e., compounds of formula II-q17, wherein R₃ is halogen.

In yet another aspect, the invention provides compounds of formulaII-q19, i.e., compounds of formula II-q17, wherein R₃ is OH, C₁-C₄alkyl, or C₁-C₄ alkoxy.

In yet still another aspect, the invention provides compounds of formulaII-q20, i.e., compounds of formula II-q17, wherein R₃ is CF₃ or OCF₃.

In still another aspect, the invention provides compounds of formulaII-q21, i.e., compounds according to any one of formulas II-q8, II-q9,II-q10, II-q11, II-q12, II-q13, or II-q14 wherein n is 0.

In another aspect, the invention provides compounds of formula II-jj,i.e., compounds of formula II, wherein R₁ is H and R₃₀ is(C₀-C₆alkyl)-COR₅.

In yet another aspect, the invention provides compounds of formulaII-kk, i.e., compounds of formula II-jj, wherein R₅ is C₁-C₆ alkoxyoptionally substituted with 1 or 2 groups that are independently OH,C₁-C₄ alkoxy, piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl, C₃-C₇cycloalkyl, —SO₂—(C₁-C₄ alkyl), —SO₂—(C₁-C₄ haloalkyl), or —SO₂-phenylwherein the cyclic portions of the above are optionally substituted at asubstitutable position with groups that are independently C₁-C₄ alkyl,C₁-C₄ alkoxy, halogen, OH, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, amino, ormono or dialkylamino.

In still yet another aspect, the invention provides compounds of formulaII-u, i.e., compounds of formula II-s, wherein R₅ is C₁-C₆ alkoxyoptionally substituted with 1 group that is piperidinyl, pyrrolidinyl,morpholinyl, or piperazinyl wherein the cyclic portions of the above areoptionally substituted at a substitutable position with groups that areindependently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, OH, C₁-C₄ haloalkyl,C₁-C₄ haloalkoxy, amino, or mono or dialkylamino.

In still another aspect, the invention provides compounds of formulaII-v, i.e., compounds of formula II-kk, wherein R₅ is C₁-C₆ alkoxyoptionally substituted with 1 group that is —SO₂—(C₁-C₄ alkyl),—SO₂—(C₁-C₄ haloalkyl), or —SO₂-phenyl wherein the cyclic portions ofthe above are optionally substituted at a substitutable position withgroups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, OH,C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, amino, or mono or dialkylamino.

In another aspect, the invention provides compounds of formula II-nn,i.e., compounds of formula II-t, wherein R₅ is C₁-C₆ alkoxy optionallysubstituted with C₃-C₇ cycloalkyl (preferably C₃-C₆ cycloalkyl, morepreferably C₃-C₅ cycloalkyl, still more preferably, cyclopropyl) whereinthe cyclic portions of the above are optionally substituted at asubstitutable position with groups that are independently C₁-C₄ alkyl,C₁-C₄ alkoxy, halogen, OH, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, amino, ormono or dialkylamino.

In still another aspect, the invention provides compounds of formulaII-x, i.e., compounds of formula II-s, wherein R₅ is OH, amino, mono ordialkylamino, or C₁-C₆ haloalkoxy.

In yet another aspect, the invention provides compounds of formula II-y,i.e., compounds of formula II-oo, wherein R₅ is amino, or mono ordi(C₁-C₆ alkyl)amino.

In yet still another aspect, the invention provides compounds of formulaII-z, i.e., compounds of formula II-s, wherein R₅ is C₁-C₆ haloalkoxyoptionally substituted with 1 OH.

In yet another aspect, the invention provides compounds of formula II-a,i.e., compounds of formula II-qq, wherein R₅ is—CH₂C(halogen)₂C(halogen)₃, -CH₂CH₂C(halogen)₃, where each halogen isindependently F or Cl.

In still another aspect, the invention provides compounds of formulaII-ss, i.e., compounds of formula II-rr, wherein R₅ is —CH₂CF₂CF₃,—CH₂CH₂CF₃.

In another aspect, the invention provides compounds of formula II-bb,i.e., compounds of formula II-z, wherein R₅ is—CH(CH₃)C(halogen)₂C(halogen)₃, —CH(CH₂halogen)₂, —CH(CH₃)C(halogen)₃,—CH(C(halogen)₃)₂, —C(CH₃)(C(halogen)₃)₂, or —CH(OH)C(halogen)₃, whereeach halogen is independently F or Cl.

In yet another aspect, the invention provides compounds of formulaII-dd, i.e., compounds of formula II-cc, wherein R₅ is —CH(CH₃)CF₂CF₃,—CH(CH₂F)₂, —CH(CH₃)CF₃, —CH(CF₃)₂, —C(CH₃)(CF₃)₂, or —CH(OH)CF₃.

In still another aspect, the invention provides compounds of formulaII-ee, i.e., compounds of formula II-cc, wherein R₅ is—C(CH₃)(C(halogen)₃)₂ preferably each halogen is F.

In still yet another aspect, the invention provides compounds of formulaII-ff, i.e., compounds of formula II-cc, wherein R₅ is—CH(OH)C(halogen)₃. In one case, the stereogenic center in R₅ has theS-configuration. In another case, the stereogenic center in R₅ has theR-configuration.

In another aspect, the invention provides compounds of formula II-gg,i.e., compounds according to any one of formulas II-r, II-s, II-t, II-u,II-v, II-w, II-x, II-y, II-z, II-aa, II-bb, II-cc, II-dd, II-ee, orII-ff wherein at least one of R₃₀ and R₄₀ is H.

In still yet another aspect, the invention provides compounds of formulaII-hh, item compounds of formula II-gg, wherein one of R₃₀ and R₄₀ ishalogen (in one aspect, F or Cl), OH, amino, mono ordi(C₁-C₄)alkylamino, hydroxy(C₁-C₄)alkyl, CF₃, or OCF₃.

In yet still another aspect, the invention provides compounds of formulaII-ii, i.e., compounds of formula II-gg, wherein both R₃₀ and R₄₀ are H.

In yet another aspect, the invention provides compounds of formulaII-ii1, i.e., compounds according to any one of formulas II-gg, II-hh,or II-ii wherein n is 1.

In yet still another aspect, the invention provides compounds of formulaII-ii2, i.e., compounds of formula II-ii1, wherein R₃ is halogen, OH,C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₂ haloalkyl, or C₁-C₂ haloalkoxy.

In still yet another aspect, the invention provides compounds of formulaII-ii3, i.e., compounds of formula II-ii2, wherein R₃ is halogen, OH,C₁-C₄ alkyl, C₁-C₄ alkoxy, CF₃, of OCF₃.

In still another aspect, the invention provides compounds of formulaI-ii4, i.e., compounds of formula II-ii3, wherein R₃ is halogen.

In yet another aspect, the invention provides compounds of formulaII-ii5, i.e., compounds of formula II-ii2, wherein R₃ is OH, C₁-C₄alkyl, or C₁-C₄ alkoxy.

In yet still another aspect, the invention provides compounds of formulaIL-ii6, i.e., compounds of formula II-ii2, wherein R₃ is CF₃ or OCF₃.

In still another aspect, the invention provides compounds of formulaII-ii7, i.e., compounds according to any one of formulas II-gg, II-hh,or II-ii wherein n is 0.

In another aspect, the invention provides compounds of formula II-ii8,i.e., compound according to formula II-r, wherein R₂₀ is (C₀-C₆alkyl)-OR₆.

In yet still another aspect, the invention provides compounds of formulaII-ii9, i.e., compounds of formula II-ii8, wherein R₆ is C₁-C₆ alkanoyl,wherein the alkyl portion of the alkanoyl group is substituted with oneor more halogens (preferably F or Cl, more preferably, F.) Or R₆ can be—(C₁-C₄ alkyl)-phenyl, —(C₁-C₄ alkanoyl)-phenyl, or phenyl, wherein thephenyl groups are optionally substituted with 1, 2, 3, 4, or 5 groupsthat are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, OH, C₁-C₄haloalkyl (such as CF₃), C₁-C₄ haloalkoxy (such as OCF₃), amino, or monoor di C₁-C₆ alkylamino.

In still yet another aspect, the invention provides compounds of formulaII-ii10, i.e., compound according to formula II-ii9, wherein R₂₀ is—(C₀-C₆ alkyl)-O—R₆.

In still yet another aspect, the invention provides compounds of formulaII-ii11, i.e., compound according to formula II-ii10, wherein R₂₀ is—(C₀-C₄ alkyl)-O—R₆.

In another aspect, the invention provides compounds of formula II-ii12,i.e., compounds according to any one of formulas II-ii8, II-ii9,II-ii10, or II-ii11, wherein at least one of R₃₀ and R₄₀ is H.

In still yet another aspect, the invention provides compounds of formulaII-ii13, i.e., compounds of formula II-ii12, wherein one of R₃₀ and R₄₀is halogen (in one aspect, F or Cl), OH, amino, mono ordi(C₁-C₄)alkylamino, hydroxy(C₁-C₄)alkyl, CF₃, or OCF₃.

In yet still another aspect, the invention provides compounds of formulaII-ii14, i.e., compounds of formula II-ii12, wherein both R₃₀ and R₄₀are H.

In yet another aspect, the invention provides compounds of formulaII-ii15, i.e., compounds according to any one of formulas II-ii8,II-ii9, II-ii10, II-ii11, II-ii12, II-ii13, or II-ii14 wherein n is 1.

In yet still another aspect, the invention provides compounds of formulaII-ii16, i.e., compounds of formula II-ii15, wherein R₃ is halogen, OH,C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₂ haloalkyl, or C₁-C₂ haloalkoxy.

In still yet another aspect, the invention provides compounds of formulaII-ii17, i.e., compounds of formula II-ii16, wherein R₃ is halogen, OH,C₁-C₄ alkyl, C₁-C₄ alkoxy, CF₃, or OCF₃.

In still another aspect, the invention provides compounds of formulaII-ii18, i.e., compounds of formula II-ii17, wherein R₃ is halogen.

In yet another aspect, the invention provides compounds of formulaII-ii19, i.e., compounds of formula II-ii17, wherein R₃ is OH, C₁-C₄alkyl, or C₁-C₄ alkoxy.

In yet still another aspect, the invention provides compounds of formulaII-ii20, i.e., compounds of formula II-ii17, wherein R₃ is CF₃ or OCF₃.

In still another aspect, the invention provides compounds of formulaII-ii21, i.e., compounds according to any one of formulas II-ii8,II-ii9, II-ii10, II-ii11, II-ii12, II-ii13, or II-ii14 wherein n is 0.

In another aspect, the invention provides compounds of formula II-jj,i.e., compounds of formula II, wherein R₁ is H and R₃₀ is —(C₀-C₆alkyl)-COR₅.

In yet another aspect, the invention provides compounds of formulaII-kk, i.e., compounds of formula II-jj, wherein R₅ is C₁-C₆ alkoxyoptionally substituted with 1 or 2 groups that are independently OH,C₁-C₄ alkoxy, piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl, C₃-C₇cycloalkyl, —SO₂—(C₁-C₄ alkyl), —SO₂—(C₁-C₄ haloalkyl), or —SO₂-phenylwherein the cyclic portions of the above are optionally substituted at asubstitutable position with groups that are independently C₁-C₄ alkyl,C₁-C₄ alkoxy, halogen, OH, C₁-C₄ haloalkoxy, C₁-C₄ haloalkoxy, amino, ormono or dialkylamino.

In still yet another aspect, the invention provides compounds of formulaII-ll, i.e., compounds of formula II-kk, wherein R₅ is C₁-C₆ alkoxyoptionally substituted with 1 group that is piperidinyl, pyrrolidinyl,morpholinyl, or piperazinyl wherein the cyclic portions of the above areoptionally substituted at a substitutable position with groups that areindependently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, OH, C₁-C₄ haloalkyl,C₁-C₄ haloalkoxy, amino, or mono or dialkylamino

In still another aspect, the invention provides compounds of formulaII-mm, i.e., compounds of formula II-kk, wherein R₅ is C₁-C₆ alkoxyoptionally substituted with 1 group that is —SO₂—(C₁-C₄ alkyl),—SO₂—(C₁-C₄ haloalkyl), or —SO₂-phenyl wherein the cyclic portions ofthe above are optionally substituted at a substitutable position withgroups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, OH,C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, amino, or mono or dialkylamino.

In another aspect, the invention provides compounds of formula II-nn,i.e., compounds of formula II-kk, wherein R₅ is C₁-C₆ alkoxy optionallysubstituted with C₃-C₇ cycloalkyl (preferably C₃-C₆ cycloalkyl, morepreferably C₃-C₅ cycloalkyl, still more preferably, cyclopropyl) whereinthe cyclic portions of the above are optionally substituted at asubstitutable position with groups that are independently C₁-C₄ alkyl,C₁-C₄ alkoxy, halogen, OH, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, amino, ormono or dialkylamino.

In still another aspect, the invention provides compounds of formulaII-oo, i.e., compounds of formula II-jj, wherein R₅ is OH, amino, monoor dialkylamino, or C₁-C₆ haloalkoxy,

In yet another aspect, the invention provides compounds of formulaII-pp, i.e., compounds of formula II-oo, wherein R₅ is amino, or mono ordi(C₁-C₆ alkyl)amino.

In yet still another aspect, the invention provides compounds of formulaII-qq, i.e., compounds of formula II-jj, wherein R₅ is C₁-C₆ haloalkoxyoptionally substituted with 1 OH.

In yet another aspect, the invention provides compounds of formulaII-rr, i.e., compounds of formula II-qq, wherein R₅ is—CH₂C(halogen)₂C(halogen)₃, —CH₂CH₂C(halogen)₃, where each halogen isindependently F or Cl.

In still another aspect, the invention provides compounds of formulaII-ss, i.e., compounds of formula II-rr, wherein R₅ is —CH₂CF₂CF₃,—CH₂CH₂CF₃.

In another aspect, the invention provides compounds of formula II-tt,i.e., compounds of formula II-iiq, wherein R₅ is—CH(CH₃)C(halogen)₂C(halogen)₃, —CH(CH₂halogen)₂, —CH(CH₃)C(halogen)₃,—CH(C(halogen)₃)₂, —C(CH₃)(C(halogen)₃)₂, or —CH(OH)C(halogen)₃, whereeach halogen is independently F or Cl.

In yet another aspect, the invention provides compounds of formulaII-uu, i.e., compounds of formula II-tt, wherein R₅ is —CH(CH₃)CF₂CF₃,—CH(CH₂F)₂, —CH(CH₃)CF₃, —CH(CF₃)₂, —C(CH₃)(CF₃)₂, or —CH(OH)CF₃.

In still another aspect, the invention provides compounds of formulaII-vv, i.e., compounds of formula II-tt, wherein R₅ is—C(CH₃)(C(halogen)₃)₂ preferably each halogen is F.

In still yet another aspect, the invention provides compounds of formulaII-ww, i.e., compounds of formula II-tt, wherein R₅ is—CH(OH)C(halogen)₃. In one case, the stereogenic center in R₅ has theS-configuration. In another case, the stereogenic center in R₅ has theR-configuration.

In another aspect, the invention provides compounds of formula II-xx,i.e., compounds according to any one of formulas II-jj, II-kk, II-ll,II-mm, II-nn, II-oo, II-pp, II-qq, II-rr, II-ss, II-tt, II-uu, II-vv, orII-ww, wherein at least one of R₂₀ and R₄₀ is H.

In still yet another aspect, the invention provides compounds of formulaII-yy, i.e., compounds of formula II-xx, wherein one of R₂₀ and R₄₀ ishalogen (in one aspect, F or Cl), OH, amino, mono ordi(C₁-C₄)alkylamino, hydroxy(C₁-C₄)alkyl, CF₃, or OCF₃.

In yet still another aspect, the invention provides compounds of formulaII-zz, i.e., compounds of formula II-xx, wherein both R₂₀ and R₄₀ are H.

In yet another aspect, the invention provides compounds of formulaII-zz1, i.e., compounds according to any one of formulas II-xx, II-yy,or II-zz wherein n is 1.

In yet still another aspect, the invention provides compounds of formulaII-zz2, i.e., compounds of formula II-zz1, wherein R₃ is halogen, OH,C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₂ haloalkyl, or C₁-C₂ haloalkoxy.

In still yet another aspect, the invention provides compounds of formulaII-zz3, i.e., compounds of formula II-zz2, wherein R₃ is halogen, OH,C₁-C₄ alkyl, C₁-C₄ alkoxy, CF₃, or OCF₃.

In still another aspect, the invention provides compounds of formulaII-zz4, i.e., compounds of formula II-zz3, wherein R₃ is halogen.

In yet another aspect, the invention provides compounds of formulaII-zz5, i.e., compounds of formula II-zz3, wherein R₃ is OH, C₁-C₄alkyl, or C₁-C₄ alkoxy.

In yet still another aspect, the invention provides compounds of formulaII-zz6, i.e., compounds of formula II-zz3, wherein R₃ is CF₃ or OCF₃.

In still another aspect, the invention provides compounds of formulaII-zz7, i.e., compounds according to any one of formulas II-xx, II-yy,or II-zz wherein n is 0.

In another aspect, the invention provides compounds of formula II-zz8,i.e., compound according to formula II, wherein R₁ is H, and R₃₀ is(C₀-C₆ alkyl)-OR₆.

In yet still another aspect, the invention provides compounds of formulaII-zz9, i.e., compounds of formula II-zz8, wherein R₆ is C₁-C₆ alkanoyl,wherein the alkyl portion of the alkanoyl group is substituted with oneor more halogens (preferably F or Cl, more preferably, F.) Or R₆ can be—(C₁-C₄ alkyl)-phenyl, —(C₁-C₄ alkanoyl)-phenyl, or phenyl, wherein thephenyl groups are optionally substituted with 1, 2, 3, 4, or 5 groupsthat are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, OH, C₁-C₄haloalkyl (such as CF₃), C₁-C₄ haloalkoxy (such as OCF₃), amino, or monoor di C₁-C₆ alkylamino.

In still yet another aspect, the invention provides compounds of formulaII-zz10, i.e., compound according to formula II-zz9, wherein R₃₀ is—(C₀-C₆ alkyl)-O—R₆.

In still yet another aspect, the invention provides compounds of formulaII-zz11, i.e., compound according to formula II-zz10, wherein R₃₀ is—(C₀-C₄ alkyl)-O—R₆.

In another aspect, the invention provides compounds of formula II-zz12,i.e., compounds according to any one of formulas II-zz8, II-zz9,II-zz10, or II-zz11, wherein at least one of R₂₀ and R₄₀ is H.

In still yet another aspect, the invention provides compounds of formulaII-zz13, i.e., compounds of formula II-zz12, wherein one of R₂₀ and R₄₀is halogen (in one aspect, F or Cl), OH, amino, mono ordi(C₁-C₄)alkylamino, hydroxy(C₁-C₄)alkyl, CF₃, or OCF₃.

In yet still another aspect, the invention provides compounds of formulaII-zz14, i.e., compounds of formula II-zz12, wherein both R₂₀ and R₄₀are H.

In yet another aspect, the invention provides compounds of formulaII-zz15, i.e., compounds according to any one of formulas II-zz8,II-zz9, II-z10, II-zz11, II-zz12, II-zz13, or II-zz14 wherein n is 1.

In yet still another aspect, the invention provides compounds of formulaII-zz16, i.e., compounds of formula II-zz15, wherein R₃ is halogen, OH,C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₂ haloalkyl, or C₁-C₂ haloalkoxy.

In still yet another aspect, the invention provides compounds of formulaII-zz17, i.e., compounds of formula II-zz16, wherein R₃ is halogen, OH,C₁-C₄ alkyl, C₁-C₄ alkoxy, CF₃, or OCF₃.

In still another aspect, the invention provides compounds of formulaII-zz18, i.e., compounds of formula II-zz17, wherein R₃ is halogen.

In yet another aspect, the invention provides compounds of formulaII-zz19, i.e., compounds of formula II-zz17, wherein R₃ is OH, C₁-C₄alkyl, or C₁-C₄ alkoxy.

In yet still another aspect, the invention provides compounds of formulaII-zz20, i.e., compounds of formula II-zz17, wherein R₃ is CF₃ or OCF₃.

In still another aspect, the invention provides compounds of formulaII-zz21, i.e., compounds according to any one of formulas II-zz8,II-zz9, II-zz10, II-zz11, II-zz12, II-zz13, or II-zz14 wherein n is 0.

In another aspect, the invention provides compounds of formula II-aaa,i.e., compounds of formula II, wherein R₁ is CH₂COOH and R₃₀ is —(C₀-C₆alkyl)-COR₅.

In yet another aspect, the invention provides compounds of formulaII-bbb, i.e., compounds of formula II-aaa, wherein R₅ is C₁-C₆ alkoxyoptionally substituted with 1 or 2 groups that are independently OH,C₁-C₄ alkoxy, piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl, C₃-C₇cycloalkyl, —SO₂—(C₁-C₄ alkyl), —SO₂—(C₁-C₄ haloalkyl), or —SO₂-phenylwherein the cyclic portions of the above are optionally substituted at asubstitutable position with groups that are independently C₁-C₄ alkyl,C₁-C₄ alkoxy, halogen, OH, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, amino, ormono or dialkylamino.

In still yet another aspect, the invention provides compounds of formulaII-ccc, i.e., compounds of formula II-bbb, wherein R₅ is C₁-C₆ alkoxyoptionally substituted with 1 group that is piperidinyl, pyrrolidinyl,morpholinyl, or piperazinyl wherein the cyclic portions of the above areoptionally substituted at a substitutable position with groups that areindependently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, OH, C₁-C₄ haloalkyl,C₁-C₄ haloalkoxy, amino, or mono or dialkylamino.

In still another aspect, the invention provides compounds of formulaII-ddd, i.e., compounds of formula II-bbb, wherein R₅ is C₁-C₆ alkoxyoptionally substituted with 1 group that is —SO₂—(C₁-C₄ alkyl),—SO₂—(C₁-C₄ haloalkyl), or —SO₂-phenyl wherein the cyclic portions ofthe above are optionally substituted at a substitutable position withgroups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, OH,C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, amino, or mono or dialkylamino.

In another aspect, the invention provides compounds of formula II-eee,i.e., compounds of formula II-bbb, wherein R₅ is C₁-C₆ alkoxy optionallysubstituted with C₃-C₇ cycloalkyl (preferably C₃-C₆ cycloalkyl, morepreferably C₃-C₅ cycloalkyl, still more preferably, cyclopropyl) whereinthe cyclic portions of the above are optionally substituted at asubstitutable position with groups that are independently C₁-C₄ alkyl,C₁-C₄ alkoxy, halogen, OH, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, amino, ofmono or dialkylamino.

In still another aspect, the invention provides compounds of formulaII-fff, i.e., compounds of formula II-aaa, wherein R₅ is OH, amino, monoor dialkylamino, or C₁-C₆ haloalkoxy.

In yet another aspects the invention provides compounds of formulaII-ggg, i.e., compounds of formula II-fff, wherein R₅ is amino, or monoor di(C₁-C₆ alkyl)amino.

In yet still another aspect, the invention provides compounds of formulaII-hhh, i.e., compounds of formula II-aaa, wherein R₅ is C₁-C₆haloalkoxy optionally substituted with 1 OH.

In yet another aspect, the invention provides compounds of formulaII-iii, i.e., compounds of formula II-hhh, wherein R₅ is—CH₂C(halogen)₂C(halogen)₃, —CH₂CH₂C(halogen)₃, where each halogen isindependently F or Cl.

In still another aspect, the invention provides compounds of formulaII-jjj, i.e., compounds of formula II-iii, wherein R₅ is —CH₂CF₂CF₃,—CH₂CH₂CF₃.

In another aspect, the invention provides compounds of formula II-kkk,i.e., compounds of formula II-hhh, wherein R₅ is—CH(CH₃)C(halogen)₂C(halogen)₃, —CH(CH₂halogen)₂, —CH(CH₃)C(halogen)₃,—CH(C(halogen)₃)₂, —C(CH₃)(C(halogen)₃)₂, or —CH(OH)C(halogen)₃, whereeach halogen is independently F or Cl.

In yet another aspect, the invention provides compounds of formulaII-lll, i.e., compounds of formula II-kkk, wherein R₅ is —CH(CH₃)CF₂CF₃,—CH(CH₂F)₂, —CH(CH₃)CF₃, —CH(CF₃)₂, —C(CH₃)(CF₃)₂, or —CH(OH)CF₃.

In still another aspect, the invention provides compounds of formulaII-mmm, i.e., compounds of formula II-kkk wherein R₅ is—C(CH₃)(C(halogen)₃)₂ preferably each halogen is F.

In still yet another aspect, the invention provides compounds of formulaII-nnn, i.e., compounds of formula II-kkk, wherein R₅ is—CH(OH)C(halogen)₃. In one case, the stereogenic center in R₅ has theS-configuration. In another case, the stereogenic center in R₅ has theR-configuration.

In another aspect, the invention provides compounds of formula II-ooo,i.e., compounds according to any one of formulas II-aaa, II-bbb, II-ccc,II-ddd, II-eee, II-fff, II-ggg, II-hhh, II-iii, II-jjj, II-kkk, II-lll,II-mmm, or II-nnn, wherein at least one of R₂₀ and R₄₀ is H.

In still yet another aspect, the invention provides compounds of formulaII-ppp, i.e., compounds of formula II-ooo, wherein one of R₂₀ and R₄₀ ishalogen (in one aspect, F or Cl), OH, amino, mono ordi(C₁-C₄)alkylamino, hydroxy(C₁-C₄)alkyl, CF₃, or OCF₃.

In yet still another aspect, the invention provides compounds of formulaII-qqq, i.e., compounds of formula II-ooo, wherein both R₂₀ and R₄₀ areH.

In yet another aspect, the invention provides compounds of formulaII-rrr, i.e., compounds according to any one of formulas II-ooo, II-ppp,or II-qqq wherein n is 1.

In yet still another aspect, the invention provides compounds of formulaII-sss, i.e., compounds of formula II-rrr, wherein R₃ is halogen, OH,C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₂ haloalkyl, or C₁-C₂ haloalkoxy.

In still yet another aspect, the invention provides compounds of formulaII-ttt, i.e., compounds of formula II-sss, wherein R₃ is halogen, OH,C₁-C₄ alkyl, C₁-C₄ alkoxy, CF₃, or OCF₃.

In still another aspect, the invention provides compounds of formulaII-uuu, i.e., compounds of formula II-ttt, wherein R₃ is halogen.

In yet another aspect, the invention provides compounds of formulaII-vvv, i.e., compounds of formula II-ttt, wherein R₃ is OH, C₁-C₄alkyl, or C₁-C₄ alkoxy.

In yet still another aspect, the invention provides compounds of formulaII-www, i.e., compounds of formula II-ttt, wherein R₃ is CF₃ or OCF₃.

In still another aspect, the invention provides compounds of formulaII-xxx, i.e., compounds according to any one of formulas II-ooo, II-ppp,or II-qqq wherein n is 0.

In another aspect, the invention provides compounds of formula II-xxx1,i.e., compound according to formula II, wherein R₁ is CH₂CO₂H, and R₃₀is (C₀-C₆ alkyl)-OR₆.

In yet still another aspect, the invention provides compounds of formulaII-xxx2, i.e., compounds of formula II-xxx1, wherein R₆ is C₁-C₆alkanoyl, wherein the alkyl portion of the alkanoyl group is substitutedwith one or more halogens (preferably F or Cl, more preferably, F.) OrR₆ can be —(C₁-C₄ alkyl)-phenyl, —(C₁-C₄ alkanoyl)-phenyl, or phenyl,wherein the phenyl groups are optionally substituted with 1, 2, 3, 4, or5 groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, OH,C₁-C₄ haloalkyl (such as CF₃), C₁-C₄ haloalkoxy (such as OCF₃), amino,or mono or di C₁-C₆ alkylamino.

In still yet another aspect, the invention provides compounds of formulaII-xxx3, i.e., compound according to formula II-xxx2, wherein R₃₀ is—(C₀-C₆ alkyl)-O—R₆.

In still yet another aspect, the invention provides compounds of formulaII-xxx4, i.e., compound according to formula II-xxx3, wherein R₃₀ is—C₀-C₄ alkyl)-O—R₆.

In another aspect, the invention provides compounds of formula II-xxx5,i.e., compounds according to any one of formulas II-xxx1, II-xxx2,II-xxx3, or II-xxx4, wherein at least one of R₂₀ and R₄₀ is H.

In still yet another aspect, the invention provides compounds of formulaII-xxx6, i.e., compounds of formula II-xxx5, wherein one of R₂₀ and R₄₀is halogen (in one aspect, F or Cl), OH, amino, mono ordi(C₁-C₄)alkylamino, hydroxy(C₁-C₄)alkyl, CF₃, or OCF₃.

In yet still another aspect, the invention provides compounds of formulaII-xxx7, i.e., compounds of formula II-xxx5, wherein both R₂₀ and R₄₀are H.

In yet another aspect, the invention provides compounds of formulaII-xxx8, i.e., compounds according to any one of formulas II-xxx1,II-xxx2, II-xxx3, II-xxx11, II-xxx4, II-xxx5, or II-xxx6 wherein n is 1.

In yet still another aspect, the invention provides compounds of formulaII-xxx9, i.e., compounds of formula II-xxx8, wherein R₃ is halogen, OH,C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₂ haloalkyl, or C₁-C₂ haloalkoxy.

In still yet another aspect, the invention provides compounds of formulaII-xxx10, i.e., compounds of formula II-xxx9, wherein R₃ is halogen, OH,C₁-C₄ alkyl, C₁-C₄ alkoxy, CF₃, or OCF₃.

In still another aspect, the invention provides compounds of formulaII-xxx11, i.e., compounds of formula II-xxx10, wherein R₃ is halogen.

In yet another aspect, the invention provides compounds of formulaII-xxx12, i.e., compounds of formula II-xxx10, wherein R₃ is OH, C₁-C₄alkyl, or C₁-C₄ alkoxy.

In yet still another aspect, the invention provides compounds of formulaII-xxx13, i.e., compounds of formula II-xxx10, wherein R₃ is CF₃ orOCF₃.

In still another aspect, the invention provides compounds of formulaII-xxx14, i.e., compounds according to any one of formulas II-xxx1,II-xxx2, II-xxx3, II-xxx4, II-xxx5, II-xxx6, or II-xxx7 wherein n is 0.

In another aspect, the invention provides compounds of formula III,i.e., compounds of formula I, where Ar is an optionally substitutednaphthyl group of the formula:

wherein:

-   n is 0, 1, or 2;-   R₁ is H or CH₂COOH;-   R₃ at each occurrence is independently halogen, OH, C₁-C₆ alkyl,    C₁-C₆ alkoxy, C₁-C₄ haloalkyl, or C₁-C₄ haloalkoxy; and-   R₂₀, R₃₀, R₄₀, and R₈₀ are independently H, —(C₀-C₆ alkyl)-COR₅,    (C₀-C₆ alkyl)-O—R₆, halogen, OH, amino, mono or dialkylamino,    hydroxyalkyl, C₁-C₄ haloalkyl, or C₁-C₄ haloalkoxy, wherein    -   R₅ is C₁-C₆ alkoxy optionally substituted with 1 or 2 groups        that are independently OH, C₁-C₄ alkoxy, piperidinyl,        pyrrolidinyl, morpholinyl, piperazinyl, C₃-C₇ cycloalkyl,        —SO₂—(C₁-C₄ alkyl), —SO₂—(C₁-C₄ haloalkyl), or —SO₂-phenyl, OH,        amino, mono or dialkylamino, or C₁-C₆ haloalkoxy optionally        substituted with 1 OH, wherein the cyclic portions of the above        are optionally substituted at a substitutable position with        groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy,        halogen, OH, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, amino, or mono        or dialkylamino;    -   and    -   R₆ is C₁-C₆ alkanoyl, phenyl C₁-C₆ alkanoyl, (C₁-C₆        alkyl)-O-phenyl, or phenyl, wherein the phenyl groups are        optionally substituted with 1, 2, 3, 4, or 5 groups that are        independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, OH, C₁-C₄        haloalkyl, C₁-C₄ haloalkoxy, amino, or mono or dialkylamino.

In another aspect, the invention provides compounds of formula III-a,i.e., compounds of formula III, wherein R₁ is H.

In still another aspect, the invention provides compounds of formulaIII-b, i.e., compounds of formula III-a, wherein R₂₀ is —(C₀-C₆alkyl)-COR₅.

In yet another aspect, the invention provides compounds of formulaIII-c, i.e., compounds of formula III-b, wherein R₅ is C₁-C₆ alkoxyoptionally substituted with 1 or 2 groups that aye independently OH,C₁-C₄ alkoxy, piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl, C₃-C₇cycloalkyl, —SO₂—(C₁-C₄ alkyl), —SO₂—(C₁-C₄ haloalkyl), or —SO₂-phenylwherein the cyclic portions of the above are optionally substituted at asubstitutable position with groups that are independently C₁-C₄ alkyl,C₁-C₄ alkoxy, halogen, OH, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, amino, ormono or dialkylamino.

In still yet another aspect the invention provides compounds of formulaIII-d, i.e., compounds of formula III-c, wherein R₅ is C₁-C₆ alkoxyoptionally substituted with 1 group that is piperidinyl, pyrrolidinyl,morpholinyl, or piperazinyl wherein the cyclic portions of the above areoptionally substituted at a substitutable position with groups that areindependently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, OH, C₁-C₄ haloalkyl,C₁-C₄ haloalkoxy, amino, or mono or dialkylamino.

In still another aspect, the invention provides compounds of formulaIII-e, i.e., compounds of formula III-c, wherein R₅ is C₁-C₆ alkoxyoptionally substituted with 1 group that is —SO₂—(C₁-C₄ alkyl),—SO₂—(C₁-C₄ haloalkyl), or —SO₂-phenyl wherein the cyclic portions ofthe above are optionally substituted at a substitutable position withgroups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, OH,C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, amino, or mono or dialkylamino.

In another aspect, the invention provides compounds of formula III-f,i.e., compounds of formula III-c, wherein R₅ is C₁-C₆ alkoxy optionallysubstituted with C₃-C₇ cycloalkyl (preferably C₃-C₆ cycloalkyl, morepreferably C₃-C₅ cycloalkyl, still more preferably, cyclopropyl) whereinthe cyclic portions of the above are optionally substituted at asubstitutable position with groups that are independently C₁-C₄ alkyl,C₁-C₄ alkoxy, halogen, OH, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, amino, ormono or dialkylamino.

In still another aspect, the invention provides compounds of formulaIII-g, i.e., compounds of formula III-b, wherein R₅ is OH, amino, monoor dialkylamino, or C₁-C₆ haloalkoxy.

In yet another aspect, the invention provides compounds of formulaIII-h, i.e., compounds of formula III-g, wherein R₅ is amino, or mono ordi(C₁-C₆ alkyl)amino.

In yet still another aspect, the invention provides compounds of formulaIII-i, i.e., compounds of formula III-b, wherein R₅ is C₁-C₆ haloalkoxyoptionally substituted with 1 OH.

In yet another aspect, the invention provides compounds of formulaIII-j, i.e., compounds of formula III-i, wherein R₅ is—CH₂C(halogen)₂C(halogen)₃, —CH₂CH₂C(halogen)₃, where each halogen isindependently F or Cl.

In still another aspect, the invention provides compounds of formulaIII-k, i.e., compounds of formula III-j, wherein R₅ is —CH₂CF₂CF₃,—CH₂CH₂CF₃.

In another aspect, the invention provides compounds of formula III-1,i.e., compounds of formula III-i, wherein R₅ is—CH(CH₃)C(halogen)₂C(halogen)₃, —CH(CH₂halogen)₂, —CH(CH₃)C(halogen)₃,—CH(C(halogen)₃)₂, —C(CH₃)(C(halogen)₃)₂, or —CH(OH)C(halogen)₃, whereeach halogen is independently F or Cl.

In yet another aspect, the invention provides compounds of formulaIII-11, i.e., compounds of formula III-i, wherein R₅ is —CH(CH₃)CF₂CF₃,—CH((CH₂F)₂, —CH(CH₃)CF₃, —CH(CF₃)₂, —C(CH₃)(CF₃)₂, or —CH(OH)CF₃.

In still another aspect, the invention provides compounds of formulaIII-m, i.e., compounds of formula III-1, wherein R₅ is—C(CH₃)(C(halogen)₃)₂ preferably each halogen is F.

In still yet another aspect, the invention provides compounds of formulaIII-n, i.e., compounds of formula III-1, wherein R₅ is—CH(OH)C(halogen)₃. In one case, the stereogenic center in R₅ has theS-configuration. In another case, the stereogenic center in R₅ has theR-configuration.

In another aspect, the invention provides compounds of formula III-o,i.e., compounds according to any one of formulas III-a, III-b, III-c,III-d, III-e, III-f III-g, III-h, III-I, III-j, III-k, III-l, III-l1,III-m, or III-n, wherein at least one of R₃₀ and R₄₀ is H; and R₈₀ is H,Cl, or OCF₃.

In still yet another aspect, the invention provides compounds of formulaIII-p, i.e., compounds of formula III-o, wherein one of R₃₀ and R₄₀ ishalogen (in one aspect, F or Cl), OH, amino, mono ordi(C₁-C₄)alkylamino, hydroxy(C₁-C₄)alkyl, CF₃, or OCF₃.

In yet still another aspect, the invention provides compounds of formulaIII-q, i.e., compounds of formula III-o, wherein both R₃₀ and R₄₀ are H.

In yet another aspect, the invention provides compounds of formulaIII-q1, i.e., compounds according to any one of formulas III-o, III-p,or III-q wherein n is 1.

In yet still another aspect, the invention provides compounds of formulaIII-q2, i.e., compounds of formula III-q1, wherein R₃ is halogen, OH,C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₂ haloalkyl, or C₁-C₂ haloalkoxy.

In still yet another aspect, the invention provides compounds of formulaIII-q3, i.e., compounds of formula III-q2, wherein R₃ is halogen, OH,C₁-C₄ alkyl, C₁-C₄ alkoxy, CF₃, or OCF₃.

In still another aspect, the invention provides compounds of formulaIII-ii4, i.e., compounds of formula III-ii3, wherein R₃ is halogen.

In yet another aspect, the invention provides compounds of formulaIII-ii5, i.e., compounds of formula III-q3, wherein R₃ is OH, C₁-C₄alkyl, or C₁-C₄ alkoxy.

In yet still another aspect, the invention provides compounds of formulaIII-ii6, i.e., compounds of formula III-ii3, wherein R₃ is CF₃ or OCF₃.

In still another aspect, the invention provides compounds of formulaIII-ii7, i.e., compounds according to any one of formulas III-o, III-p,or III-q wherein n is 0.

In another aspect, the invention provides compounds of formula III-q8,i.e., compound according to formula III-a, wherein R₂₀ is —(C₀-C₆alkyl)-O—R₆.

In yet still another aspect, the invention provides compounds of formulaIII-q9, i.e., compounds of formula III-q8, wherein R₆ is C₁-C₆ alkanoyl,wherein the alkyl portion of the alkanoyl group is substituted with oneor more halogens (preferably F or Cl, more preferably, F.) Or R₆ can be—(C₁-C₄ alkyl)-phenyl, —(C₁-C₄ alkanoyl)-phenyl, or phenyl, wherein thephenyl groups are optionally substituted with 1, 2, 3, 4, or 5 groupsthat are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, OH, C₁-C₄haloalkyl (such as CF₃), C₁-C₄ haloalkoxy (such as OCF₃), amino, or monoor di C₁-C₆ alkylamino.

In still yet another aspect, the invention provides compounds of formulaIII-q10, i.e., compound according to formula III-q9, wherein R₂₀ is—(C₀-C₆ alkyl)-O—R₆.

In still yet another aspect, the invention provides compounds of formulaIII-q11, i.e., compound according to formula III-q10, wherein R₂₀ is—(C₀-C₄ alkyl)-O—R₆.

In another aspect, the invention provides compounds of formula III-q12,i.e., compounds according to any one of formulas III-q8, III-q9,III-q10, or III-q11, wherein at least one of R₃₀ and R₄₀ is H; and R₈₀is H, Cl, or OCF₃.

In still yet another aspect, the invention provides compounds of formulaIII-q13, i.e., compounds of formula III-q12, wherein one of R₃₀ and R₄₀is halogen (in one aspect, F or Cl), OH, amino, mono ordi(C₁-C₄)alkylamino, hydroxy(C₁-C₄)alkyl, CF₃, or OCF₃.

In yet still another aspect, the invention provides compounds of formulaIII-q14, i.e., compounds of formula III-q12, wherein both R₃₀ and R₄₀are H.

In yet another aspect, the invention provides compounds of formulaIII-q15, i.e., compounds according to any one of formulas III-q8,III-q9, III-q10, III-q11, III-q12, III-q13, or III-q14 wherein n is 1.

In yet still another aspect, the invention provides compounds of formulaIII-q16, i.e., compounds of formula III-q15, wherein R₃ is halogen, OH,C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₂ haloalkyl, or C₁-C₂ haloalkoxy.

In still yet another aspect, the invention provides compounds of formulaIII-q17, i.e., compounds of formula III-q16, wherein R₃ is halogen, OH,C₁-C₄ alkyl, C₁-C₄ alkoxy, CF₃, or OCF₃.

In still another aspect, the invention provides compounds of formulaIII-q18, i.e., compounds of formula III-q17, wherein R₃ is halogen.

In yet another aspect, the invention provides compounds of formulaIII-q19, i.e., compounds of formula III-q17, wherein R₃ is OH, C₁-C₄alkyl, or C₁-C₄ alkoxy.

In yet still another aspect, the invention provides compounds of formulaIII-q20, i.e., compounds of formula III-17, wherein R₃ is CF₃ or OCF₃.

In still another aspect, the invention provides compounds of formulaIII-q21, i.e., compounds according to any one of formulas III-q8,III-q9, III-q10, III-q11, III-q12, III-q13, or III-q14 wherein n is 0.

In another aspect, the invention provides compounds of formula III-r,i.e., compounds of formula III, wherein R₁ is CH₂COOH.

In still another aspect, the invention provides compounds of formulaIII-s, i.e., compounds of formula III-r, wherein R₂₀ is —(C₀-C₆alkyl)-COR₅.

In yet another aspect, the invention provides compounds of formulaIII-t, i.e., compounds of formula III-s, wherein R₅ is C₁-C₆ alkoxyoptionally substituted with 1 or 2 groups that are independently OH,C₁-C₄ alkoxy, piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl, C₃-C₇cycloalkyl, —SO₂—(C₁-C₄ alkyl), —SO₂—(C₁-C₄ haloalkyl), or —SO₂-phenylwherein the cyclic portions of the above are optionally substituted at asubstitutable position with groups that are independently C₁-C₄ alkyl,C₁-C₄ alkoxy, halogen, OH, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, amino, ormono or dialkylamino.

In still yet another aspect, the invention provides compounds of formulaIII-u, i.e., compounds of formula III-t, wherein R₅ is C₁-C₆ alkoxyoptionally substituted with 1 group that is piperidinyl, pyrrolidinyl,morpholinyl, or piperazinyl wherein the cyclic portions of the above areoptionally substituted at a substitutable position with groups that areindependently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, OH, C₁-C₄ haloalkyl,C₁-C₄ haloalkoxy, amino, or mono or dialkylamino.

In still another, aspect, the invention provides compounds of formulaIII-v, i.e., compounds of formula III-t, wherein R₅ is C₁-C₆ alkoxyoptionally substituted with 1 group that is —SO₂—(C₁-C₄ alkyl),—SO₂—(C₁-C₄ haloalkyl), or —SO₂-phenyl wherein the cyclic portions ofthe above are optionally substituted at a substitutable position withgroups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, OH,C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, amino, or mono or dialkylamino.

In another aspect, the invention provides compounds of formula III-w,i.e., compounds of formula III-t, wherein R₅ is C₁-C₆ alkoxy optionallysubstituted with C₃-C₇ cycloalkyl (preferably C₃-C₆ cycloalkyl, morepreferably C₃-C₅ cycloalkyl, still more preferably, cyclopropyl) whereinthe cyclic portions of the above are optionally substituted at asubstitutable position with groups that are independently C₁-C₄ alkyl,C₁-C₄ alkoxy, halogen, OH, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, amino, ormono or dialkylamino

In still another aspect, the invention provides compounds of formulaIII-x, i.e., compounds of formula III-s, wherein R₅ is OH, amino, monoor dialkylamino, of C₁-C₆ haloalkoxy.

In yet another aspect, the invention provides compounds of formulaIII-y, i.e., compounds of formula III-x, wherein R₅ is amino, or mono ordi(C₁-C₆ alkyl)amino.

In yet still another aspect, the invention provides compounds of formulaIII-z, i.e., compounds of formula III-s, wherein R₅ is C₁-C₆ haloalkoxyoptionally substituted with 1 OH.

In yet another aspect, the invention provides compounds of formulaIII-aa, i.e., compounds of formula III-z, wherein R₅ is—CH₂C(halogen)₂C(halogen)₃, —CH₂CH₂C(halogen)₃, where each halogen isindependently F or Cl.

In still another aspect, the invention provides compounds of formulaIII-bb, i.e., compounds of formula III-aa, wherein R₅ is —CH₂CF₂CF₃,—CH₂CH₂CF₃.

In another aspect, the invention provides compounds of formula III-cc,i.e., compounds of formula III-z, wherein R₅ is—CH(CH₃)C(halogen)₂C(halogen)₃, —CH(CH₂halogen)₂, —CH(CH₃)C(halogen)₃,—CH(C(halogen)₃)₂, —C(CH₃)(C(halogen)₃)₂, or —CH(OH)C(halogen)₃, whereeach halogen is independently F or Cl.

In yet another aspect, the invention provides compounds of formulaIII-dd, i.e., compounds of formula III-cc, wherein R₅ is —CH(CH₃)CF₂CF₃,—CH(CH₂F)₂, —CH(CH₃)CF₃, —CH(CF₃)₂, —C(CH₃)(CF₃)₂, or —CH(OH)CF₃.

In still another aspect, the invention provides compounds of formulaIII-ee, i.e., compounds of formula III-cc wherein R₅ is—C(CH₃)(C(halogen)₃)₂ preferably each halogen is F.

In still yet another aspect, the invention provides compounds of formulaIII-ff, i.e., compounds of formula III-cc, wherein R₅ is—CH(OH)C(halogen)₃. In one case, the stereogenic center in R₅ has theS-configuration In another case, the stereogenic center in R₅ has theR-configuration.

In another aspect, the invention provides compounds of formula III-gg,i.e., compounds according to any one of formulas III-r, III-s, III-t,III-u, III-v, III-w, III-x, III-y, III-z, III-aa, III-bb, III-cc,III-dd, III-ee, or III-ff, wherein at least one of R₃₀ and R₄₀ is H; andR₈₀ is H, Cl, or OCF₃.

In still yet another aspect, the invention provides compounds of formulaIII-hh, i.e., compounds of formula III-gg, wherein one of R₃₀ and R₄₀ ishalogen (in one aspect, F or, Cl), OH, amino, mono ordi(C₁-C₄)alkylamino, hydroxy(C₁-C₄)alkyl, CF₃, or OCF₃.

In yet still another aspect, the invention provides compounds of formulaIII-ii, i.e., compounds of formula III-gg, wherein both R₃₀ and R₄₀ areH.

In yet another aspect, the invention provides compounds of formulaIII-ii1, i.e., compounds according to any one of formulas III-gg,III-hh, or III-ii wherein n is 1.

In yet still another aspect, the invention provides compounds of formulaIII-ii2, i.e., compounds of formula III-ii1, wherein R₃ is halogen, OH,C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₂ haloalkyl, or C₁-C₂ haloalkoxy.

In still yet another aspect, the invention provides compounds of formulaIII-ii3, i.e., compounds of formula III-ii2, wherein R₃ is halogen, OH,C₁-C₄ alkyl, C₁-C₄ alkoxy, CF₃, or OCF₃.

In still another aspect, the invention provides compounds of formulaIII-ii4, i.e., compounds of formula III-ii3, wherein R₃ is halogen.

In yet another aspect, the invention provides compounds of formulaIII-ii5, i.e., compounds of formula III-ii2, wherein R₃ is OH, C₁-C₄alkyl, or C₁-C₄ alkoxy.

In yet still another aspect, the invention provides compounds of formulaIII-ii6, i.e., compounds of formula III-ii2, wherein R₃ is CF₃ or OCF₃.

In still another aspect, the invention provides compounds of formulaIII-ii7, i.e., compounds according to any one of formulas III-gg,III-hh, or III-q wherein n is 0.

In another aspect, the invention provides compounds of formula III-ii8,i.e., compound according to formula III, wherein R₁ and CH₂CO₂H, and R₂₀is —(C₀-C₆ alkyl)-O—R₆.

In yet still another aspect, the invention provides compounds of formulaIII-ii9, i.e., compounds of formula III-ii8, wherein R₆ is C₁-C₆alkanoyl, wherein the alkyl portion of the alkanoyl group is substitutedwith one or more halogens (preferably F or Cl, more preferably, F.) OrR₆ can be —(C₁-C₄ alkyl)-phenyl, —(C₁-C₄ alkanoyl)-phenyl, or phenyl,wherein the phenyl groups are optionally substituted with 1, 2, 3, 4, or5 groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, OH,C₁-C₄ haloalkyl (such as CF₃), C₁-C₄ haloalkoxy (such as OCF₃), amino,or mono or di C₁-C₆ alkylamino.

In still yet another aspect, the invention provides compounds of formulaIII-ii10, i.e., compound according to formula III-ii9, wherein R₂₀ is—(C₀-C₆ alkyl)-O—R₆.

In still yet another aspect, the invention provides compounds of formulaIII-ii11, i.e., compound according to formula III-ii10, wherein R₂₀ is—(C₀-C₄ alkyl)-O—R₆.

In another aspect, the invention provides compounds of formula III-ii12,i.e., compounds according to any one of formulas III-ii8, III-ii9,III-ii10, or III-ii11, wherein at least one of R₃₀ and R₄₀ is H; and R₈₀is H, Cl, or OCF₃.

In still yet another aspect, the invention provides compounds of formulaIII-q13, i.e., compounds of formula III-ii12, wherein one of R₃₀ and R₄₀is halogen (in one aspect, F or Cl), OH, amino, mono ordi(C₁-C₄)alkylamino, hydroxy(C₁-C₄)alkyl, CF₃, or OCF₃. In yet stillanother aspect, the invention provides compounds of formula III-ii14,i.e., compounds of formula III-ii12, wherein both R₃₀ and R₄₀ ate H.

In yet another aspect, the invention provides compounds of formulaIII-ii15, i.e., compounds according to any one of formulas III-ii8,III-ii9, III-ii10, III-ii11, III-ii12, III-ii13, or III-ii14 wherein nis 1.

In yet still another aspect, the invention provides compounds of formulaIII-ii16, i.e., compounds of formula III-ii15, wherein R₃ is halogen,OH, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₂ haloalkyl, or C₁-C₂ haloalkoxy.

In still yet another aspect, the invention provides compounds of formulaIII-ii17, i.e., compounds of formula III-ii16, wherein R₃ is halogen,OH, C₁-C₄ alkyl, C₁-C₄ alkoxy, CF₃, or OCF₃.

In still another aspect, the invention provides compounds of formulaIII-ii18, i.e., compounds of formula II-ii17, wherein R₃ is halogen.

In yet another aspect, the invention provides compounds of formulaII-ii19, i.e., compounds of formula III-ii17, wherein R₃ is OH, C₁-C₄alkyl, or C₁-C₄ alkoxy.

In yet still another aspect, the invention provides compounds of formulaIII-ii20, i.e., compounds of formula III-ii17, wherein R₃ is CF₃ orOCF₃.

In still another aspect, the invention provides compounds of formulaIII-q21, i.e., compounds according to any one of formulas III-ii8,III-ii9, III-ii10, III-ii11, III-ii12, III-ii13, or III-ii14 wherein nis 0.

In another aspect, the invention provides compounds of formula III-jj,i.e., compounds of formula III, wherein R₁I is H and R₃₀ is —(C₀-C₆alkyl)-COR₅.

In yet another aspect, the invention provides compounds of formulaIII-kk, i.e., compounds of formula III-jj, wherein R₅ is C₁-C₆ alkoxyoptionally substituted with 1 or 2 groups that are independently OH,C₁-C₄ alkoxy, piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl, C₃-C₇cycloalkyl, —SO₂—(C₀-C₄ alkyl), —SO₂—(C₀-C₄ haloalkyl), or —SO₂-phenylwherein the cyclic portions of the above are optionally substituted at asubstitutable position with groups that are independently C₁-C₄ alkyl,C₁-C₄ alkoxy, halogen, OH, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, amino, ormono or dialkylamino.

In still yet another aspect, the invention provides compounds of formulaIII-ll, i.e., compounds of formula III-kk, wherein R₅ is C₁-C₆ alkoxyoptionally substituted with 1 group that is piperidinyl, pyrrolidinyl,morpholinyl, or piperazinyl wherein the cyclic portions of the above areoptionally substituted at a substitutable position with groups that areindependently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, OH, C₁-C₄ haloalkyl,C₁-C₄ haloalkoxy, amino, or mono or dialkylamino.

In still another aspect, the invention provides compounds of formulaIII-mm, i.e., compounds of formula III-kk, wherein R₅ is C₁-C₆ alkoxyoptionally substituted with 1 group that is —SO₂—(C₁-C₄ alkyl),—SO₂—(C₁-C₄ haloalkyl), or —SO₂-phenyl wherein the cyclic portions ofthe above are optionally substituted at a substitutable position withgroups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, OH,C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, amino, or mono or dialkylamino.

In another aspect, the invention provides compounds of formula III-nn,i.e., compounds of formula III-kk, wherein R₅ is C₁-C₆ alkoxy optionallysubstituted with C₃-C₇ cycloalkyl (preferably C₃-C₆ cycloalkyl, morepreferably C₃-C₅ cycloalkyl, still more preferably, cyclopropyl) whereinthe cyclic portions of the above are optionally substituted at asubstitutable position with groups that are independently C₁-C₄ alkyl,C₁-C₄ alkoxy, halogen, OH, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, amino, ormono or dialkylamino.

In still another aspect, the invention provides compounds of formulaIII-oo, i.e., compounds of formula III-jj, wherein R₅ is OH, amino, monoor dialkylamino, or C₁-C₆ haloalkoxy.

In yet another aspect, the invention provides compounds of formulaIII-pp, i.e., compounds of formula III-oo, wherein R₅ is amino, or monoor di(C₁-C₆ alkyl)amino.

In yet still another aspect, the invention provides compounds of formulaIII-qq, i.e., compounds of formula III-jj, wherein R₅ is C₁-C₆haloalkoxy optionally substituted with 1 OH.

In yet another aspect, the invention provides compounds of formulaIII-rr, i.e., compounds of formula III-qq, wherein R₅ is—CH₂C(halogen)₂C(halogen)₃, —CH₂CH₂C(halogen)₃, where each halogen isindependently F or Cl.

In still another aspect, the invention provides compounds of formulaIII-ss, i.e., compounds of formula III-rr, wherein R₅ is —CH₂CF₂CF₃,—CH₂CH₂CF₃.

In another aspect, the invention provides compounds of formula III-tt,i.e., compounds of formula III-qq, wherein R₅ is—CH(CH₃)C(halogen)₂C(halogen)₃, —CH(CH₂halogen)₂, —CH(CH₃)C(halogen)₃,—CH(C(halogen)₃)₂, —C(CH₃)(C(halogen)₃)₂, or —CH(OH)C(halogen)₃, whereeach halogen is independently F or Cl.

In yet another aspect, the invention provides compounds of formulaIII-uu, i.e., compounds of formula III-tt, wherein R₅ is —CH(CH₃)CF₂CF₃,—CH(CH₂F)₂, —CH(CH₃)CF₃, —CH(CF₃)₂, —C(CH₃)(CF₃)₂, or —CH(OH)CF₃.

In still another aspect, the invention provides compounds of formulaIII-vv, i.e., compounds of formula III-tt, wherein R₅ is—C(CH₃)(C(halogen)₃)₂ preferably each halogen is F.

In still yet another aspect, the invention provides compounds of formulaIII-ww, i.e., compounds of formula III-tt, wherein R₅ is—CH(OH)C(halogen)₃. In one case, the stereogenic center in R₅ has theS-configuration. In another case, the stereogenic center in R₅ has theR-configuration.

In another aspect, the invention provides compounds of formula III-xx,i.e., compounds according to any one of formulas III-jj, III-kk, III-ll,III-mm, III-nn, III-oo, III-pp, III-qq, III-rr, III-ss, III-tt, III-uu,III-vv, or III-ww, wherein at least one of R₂₀ and R₄₀ is H; and R₈₀ isH, Cl, or OCF₃.

In still yet another aspect, the invention provides compounds of formulaIII-yy, i.e., compounds of formula III-xx, wherein one of R₂₀ and R₄₀ ishalogen (in one aspect, F or Cl), OH, amino, mono ordi(C₁-C₄)alkylamino, hydroxy(C₁-C₄)alkyl, CF₃, or OCF₃.

In yet still another aspect, the invention provides compounds of formulaIII-zz, i.e., compounds of formula III-xx, wherein both R₂₀ and R₄₀ areH.

In yet another aspect, the invention provides compounds of formulaIII-zz1, i.e., compounds according to any one of formulas III-xx,III-yy, or III-zz wherein n is 1.

In yet still another aspect, the invention provides compounds of formulaIII-zz2, i.e., compounds of formula III-zz1, wherein R₃ is halogen, OH,C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₂ haloalkyl, or C₁-C₂ haloalkoxy.

In still yet another aspect, the invention provides compounds of formulaIII-zz3, i.e., compounds of formula III-zz2, wherein R₃ is halogen, OH,C₁-C₄ alkyl, C₁-C₄ alkoxy, CF₃, or OCF₃.

In still another aspect, the invention provides compounds of formulaIII-zz4, i.e., compounds of formula III-zz3, wherein R₃ is halogen.

In yet another aspect, the invention provides compounds of formulaIII-zz5, i.e., compounds of formula III-zz3, wherein R₃ is OH, C₁-C₄alkyl, or C₁-C₄ alkoxy.

In yet still another aspect, the invention provides compounds of formulaIII-zz6, i.e., compounds of formula III-zz3, wherein R₃ is CF₃ or OCF₃.

In still another aspect, the invention provides compounds of formulaIII-zz7, i.e., compounds according to any one of formulas III-xx,III-yy, or III-zz wherein n is 0.

In another aspect, the invention provides compounds of formula III-zz8,i.e., compound according to formula III, wherein R₁ is H and R₃₀ is—(C₀-C₆ alkyl)-O—R₆.

In yet still another aspect, the invention provides compounds of formulaIII-zz9, i.e., compounds of formula III-zz8, wherein R₆ is C₁-C₆alkanoyl, wherein the alkyl portion of the alkanoyl group is substitutedwith one or more halogens (preferably F or Cl, more preferably, F.) OrR₆ can be —(C₁-C₄ alkyl)-phenyl, —(C₁-C₄ alkanoyl)-phenyl, or phenyl,wherein the phenyl groups are optionally substituted with 1, 2, 3, 4, or5 groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, OH,C₁-C₄ haloalkyl (such as CF₃), C₁-C₄ haloalkoxy (such as OCF₃), amino,or mono or di C₁-C₆ alkylamino.

In still yet another aspect, the invention provides compounds of formulaIII-zz10, i.e., compound according to formula III-zz9, wherein R₃₀ is—(C₀-C₆ alkyl)-O—R₆.

In still yet another aspect, the invention provides compounds of formulaIII-zz11, i.e., compound according to formula III-zz10, wherein R₃₀ is—(C₀-C₄ alkyl)-O—R₆.

In another aspect, the invention provides compounds of formula III-zz12,i.e., compounds according to any one of formulas III-zz8, III-zz9,III-zz10, or III-zz11, wherein at least one of R₂₀ and R₄₀ is H; and R₈₀is H, Cl, or OCF₃.

In still yet another aspect, the invention provides compounds of formulaIII-zz13, i.e., compounds of formula III-zz12, wherein one of R₂₀ andR₄₀ is halogen (in one aspect, F or Cl), OH, amino, mono ordi(C₁-C₄)alkylamino, hydroxy(C₁-C₄)alkyl, CF₃, or OCF₃.

In yet still another aspect, the invention provides compounds of formulaIII-zz14, i.e., compounds of formula III-zz12, wherein both R₂₀ and R₄₀are H.

In yet another aspect, the invention provides compounds of formulaIII-zz15, i.e., compounds according to any one of formulas III-zz8,III-zz9, III-z10, III-zz11, III-zz12, III-zz13, or III-zz14 wherein n is1.

In yet still another aspect, the invention provides compounds of formulaIII-zz16, i.e., compounds of formula III-zz15, wherein R₃ is halogen,OH, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₂ haloalkyl, or C₁-C₂ haloalkoxy.

In still yet another aspect, the invention provides compounds of formulaIII-zz17, i.e., compounds of formula III-zz16, wherein R₃ is halogen,OH, C₁-C₄ alkyl, C₁-C₄ alkoxy, CF₃, or OCF₃.

In still another aspect, the invention provides compounds of formulaIII-zz18, i.e., compounds of formula III-zz17, wherein R₃ is halogen.

In yet another aspect, the invention provides compounds of formulaIII-zz19, i.e., compounds of formula III-zz17, wherein R₃ is OH, C₁-C₄alkyl, or C₁-C₄ alkoxy.

In yet still another aspect, the invention provides compounds of formulaIII-zz20, i.e., compounds of formula III-zz17, wherein R₃ is CF₃ orOCF₃.

In still another aspect, the invention provides compounds of formulaIII-zz21, i.e., compounds according to any one of formulas III-zz8,III-zz9, III-zz10, III-zz11, III-zz12, III-zz13, or III-zz14 wherein nis 0.

In another aspect, the invention provides compounds of formula III-aaa,i.e., compounds of formula III, wherein R₁ is CH₂COOH and R₃₀ is —(C₀-C₆alkyl)-COR₅.

In yet another aspect, the invention provides compounds of formulaIII-bbb, i.e., compounds of formula III-aaa, wherein R₅ is C₁-C₆ alkoxyoptionally substituted with 1 or 2 groups that are independently OH,C₁-C₄ alkoxy, piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl, C₃-C₇cycloalkyl, —SO₂—(C₁-C₄ alkyl), —SO₂—(C₁-C₄ haloalkyl), or —SO₂-phenylwherein the cyclic portions of the above ate optionally substituted at asubstitutable position with groups that are independently C₁-C₄ alkyl,C₁-C₄ alkoxy, halogen, OH, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, amino, ormono or dialkylamino.

In still yet another aspect, the invention provides compounds of formulaIII-ccc, i.e., compounds of formula III-bbb, wherein R₅ is C₁-C₆ alkoxyoptionally substituted with 1 group that is piperidinyl, pyrrolidinyl,morpholinyl, or piperazinyl wherein the cyclic portions of the above areoptionally substituted at a substitutable position with groups that areindependently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, OH, C₁-C₄ haloalkyl,C₁-C₄ haloalkoxy, amino, or mono or dialkylamino.

In still another aspect, the invention provides compounds of formulaIII-ddd, i.e., compounds of formula III-bbb, wherein R₅ is C₁-C₆ alkoxyoptionally substituted with 1 group that is —SO₂—(C₁-C₄ alkyl),—SO₂—(C₁-C₄ haloalkyl), or —SO₂-phenyl wherein the cyclic portions ofthe above are optionally substituted at a substitutable position withgroups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, OH,C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, amino, or mono or dialkylamino.

In another aspect, the invention provides compounds of formula III-eee,i.e., compounds of formula III-bbb, wherein R₅ is C₁-C₆ alkoxyoptionally substituted with C₃-C₇ cycloalkyl (preferably C₃-C₆cycloalkyl, more preferably C₃-C₅ cycloalkyl, still more preferably,cyclopropyl) wherein the cyclic portions of the above are optionallysubstituted at a substitutable position with groups that areindependently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, OH, C₁-C₄ haloalkyl,C₁-C₄ haloalkoxy, amino, or mono or dialkylamino.

In still another aspect, die invention provides compounds of formulaIII-fff, i.e., compounds of formula III-aaa, wherein R₅ is OH, amino,mono or dialkylamino, or C₁-C₆ haloalkoxy.

In yet another aspect, the invention provides compounds of formulaIII-ggg, i.e., compounds of formula III-fff, wherein R₅ is amino, ormono or di(C₁-C₆ alkyl)amino.

In yet still another aspect, the invention provides compounds of formulaIII-hhh, i.e., compounds of formula III-aaa, wherein R₅ is C₁-C₆haloalkoxy optionally substituted with 1 OH.

In yet another aspect, the invention provides compounds of formulaIII-iii, i.e., compounds of formula III-hhh, wherein R₅ is—CH₂C(halogen)₂C(halogen)₃, —CH₂CH₂C(halogen)₃, where each halogen isindependently F or Cl.

In still another aspect, the invention provides compounds of formulaIII-jjj, i.e., compounds of formula III-iii, wherein R₅ is —CH₂CF₂CF₃,—CH₂CH₂CF₃.

In another aspect, the invention provides compounds of formula III-kkk,i.e., compounds of formula III-hhh, wherein R₅ is—CH(CH₃)C(halogen)₂C(halogen)₃, —CH(CH₂halogen)₂, —CH(CH₃)C(halogen)₃,—CH(C(halogen)₃)₂, —C(CH₃)(C(halogen)₃)₂, or —CH(OH)C(halogen)₃, whereeach halogen is independently F or Cl.

In yet another aspect, the invention provides compounds of formulaIII-lll, i.e., compounds of formula III-kkk, wherein R₅ is—CH(CH₃)CF₂CF₃, —CH(CH₂F)₂, —CH(CH₃)CF₃, —CH(CF₃)₂, —C(CH₃)(CF₃)₂, or—CH(OH)CF₃.

In still another aspect, the invention provides compounds of formulaIII-mmm, i.e., compounds of formula III-kkk wherein R₅ is—C(CH₃)(C(halogen)₃)₂ preferably each halogen is F.

In still yet another aspect, the invention provides compounds of formulaIII-nnn, i.e., compounds of formula III-kkk, wherein R₅ is—CH(OH)C(halogen)₃. In one case, the stereogenic center in R₅ has theS-configuration. In another case, the stereogenic center in R₅ has theR-configuration.

In another aspect, the invention provides compounds of formula III-ooo,i.e., compounds according to any one of formulas III-aaa, III-bbb,III-ccc, III-ddd, III-eee, III-fff, III-ggg, III-hhh, III-iii, III-jjj,III-kkk, III-lll, III-mmm, or III-nnn, wherein at least one of R₃₀ andR₄₀ is H; and R₈₀ is H, Cl, or OCF₃.

In still yet another aspect, the invention provides compounds of formulaIII-ppp, i.e., compounds of formula III-ooo, wherein one of R₂₀ and R₄₀is halogen (in one aspect, F or Cl), OH, amino, mono ordi(C₁-C₄)alkylamino, hydroxy(C₁-C₄)alkyl, CF₃, or OCF₃.

In yet still another aspect, the invention provides compounds of formulaIII-qqq, i.e., compounds of formula III-ooo, wherein both R₂₀ and R₄₀are H.

In yet another aspect, the invention provides compounds of formulaIII-rrr, i.e., compounds according to any one of formulas III-ooo,III-ppp, or III-qqq wherein n is 1.

In yet still another aspect, the invention provides compounds of formulaIII-sss, i.e., compounds of formula III-rrr, wherein R₃ is halogen, OH,C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₂ haloalkyl, or C₁-C₂ haloalkoxy.

In still yet another aspect, the invention provides compounds of formulaIII-ttt, i.e., compounds of formula III-sss, wherein R₃ is halogen, OH,C₁-C₄ alkyl, C₁-C₄ alkoxy, CF₃, or OCF₃.

In still another aspect, the invention provides compounds of formulaIII-uuu, i.e., compounds of formula III-ttt, wherein R₃ is halogen.

In yet another aspect, the invention provides compounds of formulaIII-vvv, i.e., compounds of formula III-ttt, wherein R₃ is OH, C₁-C₄alkyl, or C₁-C₄ alkoxy.

In yet still another aspect, the invention provides compounds of formulaIII-www, i.e., compounds of formula III-ttt, wherein R₃ is CF₃ or OCF₃.

In still another aspect, the invention provides compounds of formulaIII-xxx, i.e., compounds according to any one of formulas III-ooo,III-ppp, or III-qqq wherein n is 0.

In another aspect, the invention provides compounds of formula III-xxx1,i.e., compound according to formula III, wherein R₁ is CH₂CO₂H and R₃₀is —(C₀-C₆ alkyl)-O—R₆.

In yet still another aspect, the invention provides compounds of formulaIII-xxx2, i.e., compounds of formula III-xxx1, wherein R₆ is C₁-C₆alkanoyl, wherein the alkyl portion of the alkanoyl group is substitutedwith one or more halogens (preferably F or Cl, more preferably, F.) OrR₆ can be —(C₁-C₄ alkyl)-phenyl, —(C₁-C₄ alkanoyl)-phenyl, or phenyl,wherein the phenyl groups are optionally substituted with 1, 2, 3, 4, or5 groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, OH,C₁-C₄ haloalkyl (such as CF₃), C₁-C₄ haloalkoxy (such as OCF₃), amino,or mono or di C₁-C₆ alkylamino.

In still yet another aspect, the invention provides compounds of formulaIII-xxx3, i.e., compound according to formula III-xxx2, wherein R₃₀ is—(C₀-C₆ alkyl)-O—R₆.

In still yet another aspect, the invention provides compounds of formulaIII-xxx4, i.e., compound according to formula III-xxx3, wherein R₃₀ is—(C₀-C₄ alkyl)-O—R₆.

In another aspect, the invention provides compounds of formula III-xxx5,i.e., compounds according to any one of formulas III-xxx1, III-xxx2,III-xxx3, or III-xxx4, wherein at least one of R₂₀ and R₄₀ is H; and R₈₀is H, Cl, or OCF₃.

In still yet another aspect, the invention provides compounds of formulaIII-xxx6, i.e., compounds of formula III-xxx5, wherein one of R₂₀ andR₄₀ is halogen (in one aspect, F or Cl), OH, amino, mono ordi(C₁-C₄)alkylamino, hydroxy(C₁-C₄)alkyl, CF₃, or OCF₃.

In yet still another aspect, the invention provides compounds of formulaIII-xxx7, i.e., compounds of formula III-xxx5, wherein both R₂₀ and R₄₀are H.

In yet another aspect, the invention provides compounds of formulaIII-xxx8, i.e., compounds according to any one of formulas III-xxx1,III-xxx2, III-xxx3, III-xxx4, III-xxx5, III-xxx6, or III-xxx7, wherein nis 1.

In yet still another aspect, the invention provides compounds of formulaIII-xxx9, i.e., compounds of formula III-xxx8, wherein R₃ is halogen,OH, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₂ haloalkyl, or C₁-C₂ haloalkoxy.

In still yet another aspect, the invention provides compounds of formulaIII-xxx10, i.e., compounds of formula III-xxx9, wherein R₃ is halogen,OH, C₁-C₄ alkyl, C₁-C₄ alkoxy, CF₃, or OCF₃.

In still another aspect, the invention provides compounds of formulaIII-xxx11, i.e., compounds of formula III-xxx10, wherein R₃ is halogen.

In yet another aspect, the invention provides compounds of formulaIII-xxx12, i.e., compounds of formula III-xxx10, wherein R₃ is OH, C₁-C₄alkyl, or C₁-C₄ alkoxy.

In yet still another aspect, the invention provides compounds of formulaIII-xxx13, i.e., compounds of formula III-xxx10, wherein R₃ is CF₃ orOCF₃.

In still another aspect, the invention provides compounds of formulaIII-xxx10, i.e., compounds according to any one of formulas III-xxx1,III-xxx2, III-xxx3, III-xxx4, III-xxx5, III-xxx6, or III-xxx7 wherein nis 0.

In another aspect, the invention provides compounds and salts of formulaIV, i.e., compounds of formula I having the formula:

wherein:

-   n is 0, 1, or 2;-   p is 1 or 2;-   R₁ is H or CH₂COOH;-   R₃ at each occurrence is independently halogen, OH, C₁-C₆ alkyl,    C₁-C₆ alkoxy, C₁-C₄ haloalkyl, or C₁-C₄ haloalkoxy; and-   R₂₀, R₃₀, and R₄₀ are independently H, —(C₀-C₆ alkyl)-COR₅, —(C₁-C₆    alkyl)-COR₅, (C₀-C₆ alkyl)-O—R₆, halogen, OH, amino, mono or    dialkylamino, hydroxyalkyl, C₁-C₄ haloalkyl, or C₁-C₄ haloalkoxy,    wherein    -   R₅ is C₁-C₆ alkoxy optionally substituted with 1 or 2 groups        that are independently OH, C₁-C₄ alkoxy, piperidinyl,        pyrrolidinyl, morpholinyl, piperazinyl, C₃-C₇ cycloalkyl,        —SO₂—(C₁-C₄ alkyl), —SO₂—(C₁-C₄ haloalkyl), or —SO₂-phenyl, OH,        amino, mono or dialkylamino, or C₁-C₆ haloalkoxy optionally        substituted with 1 OH, wherein the cyclic portions of the above        are optionally substituted at a substitutable position with        groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy,        halogen, OH, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, amino, or mono        or dialkylamino;    -   and    -   R₆ is C₁-C₆ alkanoyl, phenyl C₁-C₆ alkanoyl, (C₁-C₆        alkyl)-O-phenyl, phenyl C₁-C₆ alkyl, or phenyl, wherein the        alkyl portions of the alkanoyl groups are optionally substituted        with one or more halogens and wherein the phenyl groups are        optionally substituted with 1, 2, 3, 4, or 5 groups that are        independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, OH, C₁-C₄        haloalkyl, C₁-C₄ haloalkoxy, amino, or mono or dialkylamino.

In another aspect, the invention provides compounds of formula IV-a,i.e., compounds of formula IV, wherein R₁ is H.

In still another aspect, the invention provides compounds of formulaIV-b, i.e., compounds of formula IV-a, wherein R₂₀ is —(C₀-C₆alkyl)-COR₅.

In yet another aspect, the invention provides compounds of formula IV-c,i.e., compounds of formula IV-b, wherein R₅ is C₁-C₆ alkoxy optionallysubstituted with 1 or 2 groups that are independently OH, C₁-C₄ alkoxy,piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl, C₃-C₇ cycloalkyl,—SO₂—(C₁-C₄ alkyl), —SO₂—(C₁-C₄ haloalkyl), or —SO₂-phenyl wherein thecyclic portions of the above are optionally substituted at asubstitutable position with groups that are independently C₁-C₄ alkyl,C₁-C₄ alkoxy, halogen, OH, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, amino, ormono or dialkylamino.

In still yet another aspect, the invention provides compounds of formulaIV-d, i.e., compounds of formula IV-c, wherein R₅ is C₁-C₆ alkoxyoptionally substituted with 1 group that is piperidinyl, pyrrolidinyl,morpholinyl, or piperazinyl wherein the cyclic portions of the above areoptionally substituted at a substitutable position with groups that areindependently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, OH, C₁-C₄ haloalkyl,C₁-C₄ haloalkoxy, amino, or mono or dialkylamino.

In still another aspect, the invention provides compounds of formulaIV-e, i.e., compounds of formula IV-c, wherein R₅ is C₁-C₆ alkoxyoptionally substituted with 1 group that is —SO₂—(C₁-C₄ alkyl),—SO₂—(C₁-C₄ haloalkyl), or —SO₂-phenyl wherein the cyclic portions ofthe above are optionally substituted at a substitutable position withgroups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, OH,C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, amino, or mono or dialkylamino.

In another aspect, the invention provides compounds of formula IV-f,i.e., compounds of formula IV-c, wherein R₅ is C₁-C₆ alkoxy optionallysubstituted with C₃-C₇ cycloalkyl (preferably C₃-C₆ cycloalkyl, morepreferably C₃-C₅ cycloalkyl, still more preferably, cyclopropyl) whereinthe cyclic portions of the above are optionally substituted at asubstitutable position with groups that are independently C₁-C₄ alkyl,C₁-C₄ alkoxy, halogen, OH, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, amino, ormono or dialkylamino.

In still another aspect, the invention provides compounds of formulaIV-g, i.e., compounds of formula IV-b, wherein R₅ is OH, amino, mono ordialkylamino, or C₁-C₆ haloalkoxy.

In yet another aspect, the invention provides compounds of formula IV-h,i.e., compounds of formula IV-g, wherein R₅ is amino, or mono ordi(C₁-C₆ alkyl)amino.

In yet still another aspect, the invention provides compounds of formulaIV-i, i.e., compounds of formula IV-b, wherein R₅ is C₁-C₆ haloalkoxyoptionally substituted with 1 OH.

In yet another aspect, the invention provides compounds of formula IV-j,i.e., compounds of formula IV-i, wherein R₅ is—CH₂C(halogen)₂C(halogen)₃, —CH₂CH₂C(halogen)₃, where each halogen isindependently F or Cl.

In still another aspect, the invention provides compounds of formulaIV-k, i.e., compounds of formula IV-j, wherein R₅ is —CH₂CF₂CF₃,—CH₂CH₂CF₃.

In another aspect, the invention provides compounds of formula IV-l,i.e., compounds of formula IV-i, wherein R₅ is—CH(CH₃)C(halogen)₂C(halogen)₃, —CH(CH₂halogen)₂, —CH(CH₃)C(halogen)₃,—CH(C(halogen)₃)₂, —C(CH₃)(C(halogen)₃)₂, or —CH(OH)C(halogen)₃, whereeach halogen is independently F or Cl.

In yet another aspect, the invention provides compounds of formulaIV-l1, i.e., compounds of formula IV-i, wherein R₅ is —CH(CH₃)CF₂CF₃,—CH(CH₂F)₂, —CH(CH₃)CF₃, —CH(CF₃)₂, —C(CH₃)(CF₃)₂, or —CH(OH)CF₃.

In still another aspect, the invention provides compounds of formulaIV-m, i.e., compounds of formula IV-l, wherein R₅ is—C(CH₃)(C(halogen)₃)₂ preferably each halogen is F.

In still yet another aspect, the invention provides compounds of formulaIV-n, i.e., compounds of formula IV-l, wherein R₅ is —CH(OH)C(halogen)₃.In one case, the stereogenic center in R₅ has the S-configuration. Inanother case, the stereogenic center in R₅ has the R-configuration.

In another aspect, the invention provides compounds of formula IV-o,i.e., compounds according to any one of formulas IV-a, IV-b, IV-c, IV-d,IV-e, IV-f, IV-g, IV-h, IV-i, IV-j, IV-k, IV-l, IV-l1, IV-m, or IV-n,wherein at least one of R₃₀ and R₄₀ is H.

In still yet another aspect, the invention provides compounds of formulaIV-p, i.e., compounds of formula IV-o, wherein one of R₃₀ and R₄₀ ishalogen (in one aspect, F or Cl), OH, amino, mono ordi(C₁-C₄)alkylamino, hydroxy(C₁-C₄)alkyl, CF₃, or OCF₃.

In yet still another aspect, the invention provides compounds of formulaIV-q, i.e., compounds of formula IV-o, wherein both R₃₀ and R₄₀ are H.

In yet another aspect, the invention provides compounds of formulaIV-q1, i.e., compounds according to any one of formulas IV-o, IV-p, orIV-q wherein n is 1.

In yet still another aspect, the invention provides compounds of formulaIV-q2, i.e., compounds of formula IV-q1, wherein R₃ is halogen, OH,C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₂ haloalkyl, or C₁-C₂ haloalkoxy.

In still yet another aspect, the invention provides compounds of formulaIV-q3, i.e., compounds of formula IV-q2, wherein R₃ is halogen, OH,C₁-C₄ alkyl, C₁-C₄ alkoxy, CF₃, or OCF₃.

In still another aspect, the invention provides compounds of formulaIV-q4, i.e., compounds of formula IV-q3, wherein R₃ is halogen.

In yet another aspect, the invention provides compounds of formulaIV-q5, i.e., compounds of formula IV-q3, wherein R₃ is OH, C₁-C₄ alkyl,or C₁-C₄ alkoxy.

In yet still another aspect, the invention provides compounds of formulaIV-q6, i.e., compounds of formula IV-q3, wherein R₃ is CF₃ or OCF₃.

In still another aspect, the invention provides compounds of formulaIV-q7, i.e., compounds according to any one of formulas IV-o, IV-p, orIV-q wherein n is 0.

In another aspect, the invention provides compounds of formula IV-q8,i.e., compound according to formula IV-a, wherein R₂₀ is (C₀-C₆alkyl)-OR₆.

In yet still another aspect, the invention provides compounds of formulaIV-q9, i.e., compounds of formula IV-q8, wherein R₆ is C₁-C₆ alkanoyl,wherein the alkyl portion of the alkanoyl group is substituted with oneor more halogens (preferably F or Cl, more preferably, F.) Or R₆ can be—(C₁-C₄ alkyl)-phenyl, —(C₁-C₄ alkanoyl)-phenyl, or phenyl, wherein thephenyl groups are optionally substituted with 1, 2, 3, 4, or 5 groupsthat are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, OH, C₁-C₄haloalkyl (such as CF₃), C₁-C₄ haloalkoxy (such as OCF₃), amino, or monoor di C₁-C₆ alkylamino.

In still yet another aspect, the invention provides compounds of formulaIV-q10, i.e., compound according to formula IV-q9, wherein R₂₀ is—(C₀-C₆ alkyl)-O—R₆.

In still yet another aspect, the invention provides compounds of formulaIV-q11, i.e., compound according to formula IV-q10, wherein R₂₀ is—(C₀-C₄ alkyl)-O—R₆.

In another aspect, the invention provides compounds of formula IV-q12,i.e., compounds according to any one of formulas IV-q8, IV-q9, IV-q10,or IV-q11, wherein at least one of R₃₀ and R₄₀ is H.

In still yet another aspect, the invention provides compounds of formulaIV-q13, i.e., compounds of formula IV-q12, wherein one of R₃₀ and R₄₀ ishalogen (in one aspect, F or Cl), OH, amino, mono ordi(C₁-C₄)alkylamino, hydroxy(C₁-C₄)alkyl, CF₃, or OCF₃.

In yet still another aspect, the invention provides compounds of formulaIV-q14, i.e., compounds of formula IV-q12, wherein both R₃₀ and R₄₀ areH.

In yet another aspect, the invention provides compounds of formulaIV-q15, i.e., compounds according to any one of formulas IV-q8, IV-q9,IV-q10, IV-q11, IV-q12, IV-q13, ox IV-q14 wherein n is 1.

In yet still another aspect, the invention provides compounds of formulaIV-q16, i.e., compounds of formula IV-q15, wherein R₃ is halogen, OH,C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₂ haloalkyl, or C₁-C₂ haloalkoxy.

In still yet another aspect, the invention provides compounds of formulaIV-q17, i.e., compounds of formula IV-q16, wherein R₃ is halogen, OH,C₁-C₄ alkyl, C₁-C₄ alkoxy, CF₃, or OCF₃.

In still another aspect, the invention provides compounds of formulaIV-q18, i.e., compounds of formula IV-q17, wherein R₃ is halogen.

In yet another aspect, the invention provides compounds of formulaIV-q19, i.e., compounds of formula IV-q17, wherein R₃ is OH, C₁-C₄alkyl, or C₁-C₄ alkoxy.

In yet still another aspect, the invention provides compounds of formulaIV-q20, i.e., compounds of formula IV-q17, wherein R₃ is CF₃ or OCF₃.

In still another aspect, the invention provides compounds of formulaIV-q21, i.e., compounds according to any one of formulas IV-q8, IV-q9,IV-q10, IV-q11, IV-q12, IV-q13, or IV-q14 wherein n is 0.

In another aspect, the invention provides compounds of formula IV-r,i.e., compounds of formula IV, wherein R₁ is CH₂COOH.

In still another aspect, the invention provides compounds of formulaIV-s, i.e., compounds of formula IV-r, wherein R₂₀ is —(C₀-C₆alkyl)-COR₅.

In yet another aspect, the invention provides compounds of formula IV-t,i.e., compounds of formula IV-s, wherein R₅ is C₁-C₆ alkoxy optionallysubstituted with 1 or 2 groups that are independently OH, C₁-C₄ alkoxy,piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl, C₃-C₇ cycloalkyl,—SO₂—(C₁-C₄ alkyl), —SO₂—(C₁-C₄ haloalkyl), or —SO₂-phenyl wherein thecyclic portions of the above ate optionally substituted at asubstitutable position with groups that are independently C₁-C₄ alkyl,C₁-C₄ alkoxy, halogen, OH, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, amino, ormono or dialkylamino.

In still yet another aspect, the invention provides compounds of formulaIV-u, i.e., compounds of formula IV-t, wherein R₅ is C₁-C₆ alkoxyoptionally substituted with 1 group that is piperidinyl, pyrrolidinyl,morpholinyl, or piperazinyl wherein the cyclic portions of the above areoptionally substituted at a substitutable position with groups that areindependently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, OH, C₁-C₄ haloalkyl,C₁-C₄ haloalkoxy, amino, or mono or dialkylamino.

In still another aspect, the invention provides compounds of formulaIV-v, i.e., compounds of formula IV-t, wherein R₅ is C₁-C₆ alkoxyoptionally substituted with 1 group that is —SO₂—(C₁-C₄ alkyl),—SO₂—(C₁-C₄ haloalkyl), or —SO₂-phenyl wherein the cyclic portions ofthe above are optionally substituted at a substitutable position withgroups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, OH,C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, amino, or mono or dialkylamino.

In another aspect, the invention provides compounds of formula IV-w,i.e., compounds of formula IV-t, wherein R₅ is C₁-C₆ alkoxy optionallysubstituted with C₃-C₇ cycloalkyl (preferably C₃-C₆ cycloalkyl, morepreferably C₃-C₅ cycloalkyl, still more preferably, cyclopropyl) whereinthe cyclic portions of the above are optionally substituted at asubstitutable position with groups that are independently C₁-C₄ alkyl,C₁-C₄ alkoxy, halogen, OH, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, amino, ormono or dialkylamino.

In still another aspect, the invention provides compounds of formulaIV-x, i.e., compounds of formula IV-s, wherein R₅ is OH, amino, mono ordialkylamino, or C₁-C₆ haloalkoxy.

In yet another aspect, the invention provides compounds of formula IV-y,i.e., compounds of formula IV-x, wherein R₅ is amino, or mono ordi(C₁-C₆ alkyl)amino.

In yet still another aspect, the invention provides compounds of formulaIV-z, i.e., compounds of formula IV-s, wherein R₅ is C₁-C₆ haloalkoxyoptionally substituted with 1 OH.

In yet another aspect, the invention provides compounds of formulaIV-aa, i.e., compounds of formula IV-z, wherein R₅ is—CH₂C(halogen)₂C(halogen)₃, —CH₂CH₂C(halogen)₃, where each halogen isindependently F or Cl.

In still another aspect, the invention provides compounds of formulaIV-bb, i.e., compounds of formula IV-aa, wherein R₅ is —CH₂CF₂CF₃,—CH₂CH₂CF₃.

In another aspect, the invention provides compounds of formula IV-cc,i.e., compounds of formula IV-z, wherein R₅ is—CH(CH₃)C(halogen)₂C(halogen)₃, —CH(CH₂halogen)₂, —CH(CH₃)C(halogen)₃,—CH(C(halogen)₃)₂, —C(CH₃)(C(halogen)₃)₂, or —CH(OH)C(halogen)₃, whereeach halogen is independently F or Cl.

In yet another aspect, the invention provides compounds of formulaIV-dd, i.e., compounds of formula IV-cc, wherein R₅ is —CH(CH₃)CF₂CF₃,—CH(CH₂F)₂, —CH(CH₃)CF₃, —CH(CF₃)₂, —C((CH₃)(CF₃)₂, or —CH(OH)CF₃.

In still another aspect, the invention provides compounds of formulaIV-ee, i.e., compounds of formula IV-cc wherein R₅ is—C(CH₃)(C(halogen)₃)₂ preferably each halogen is F.

In still yet another aspect, the invention provides compounds of formulaIV-ff, i.e., compounds of formula IV-cc, wherein R₅ is—CH(OH)C(halogen)₃. In one case, the stereogenic center in R₅ has theS-configuration In another case, the stereogenic center in R₅ has theR-configuration.

In another aspect, the invention provides compounds of formula IV-gg,i.e., compounds according to any one of formulas IV-r, IV-s, IV-t, IV-u,IV-v, IV-w, IV-x, IV-y, IV-z, IV-aa, IV-bb, IV-cc, IV-dd, IV-ee, orIV-ff, wherein at least one of R₃₀ and R₄₀ is H.

In still yet another aspect, the invention provides compounds of formulaIV-hh, i.e., compounds of formula IV-gg, wherein one of R₃₀ and R₄₀ ishalogen (in one aspect, F or Cl), OH, amino, mono ordi(C₁-C₄)alkylamino, hydroxy(C₁-C₄)alkyl, CF₃, or OCF₃.

In yet still another aspect, the invention provides compounds of formulaIV-ii, i.e., compounds of formula IV-gg, wherein both R₃₀ and R₄₀ are H.

In yet another aspect, the invention provides compounds of formulaIV-ii1, i.e., compounds according to any one of formulas IV-gg, IV-hh,or IV-ii wherein n is 1.

In yet still another aspect, the invention provides compounds of formulaIV-ii2, i.e., compounds of formula IV-ii1, wherein R₃ is halogen, OH,C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₂ haloalkyl, or C₁-C₂ haloalkoxy.

In still yet another aspect, the invention provides compounds of formulaIV-ii3, i.e., compounds of formula IV-ii2, wherein R₃ is halogen, OH,C₁-C₄ alkyl, C₁-C₄ alkoxy, CF₃, or OCF₃.

In still another aspect, the invention provides compounds of formulaIV-ii4, i.e., compounds of formula IV-ii3, wherein R₃ is halogen.

In yet another aspect, the invention provides compounds of formulaIV-ii5, i.e., compounds of formula IV-ii2, wherein R₃ is OH, C₁-C₄alkyl, or C₁-C₄ alkoxy.

In yet still another aspect, the invention provides compounds of formulaIV-ii6, i.e., compounds of formula IV-ii2, wherein R₃ is CF₃ or OCF₃.

In still another aspect, the invention provides compounds of formulaIV-ii7, i.e., compounds according to any one of formulas IV-gg, IV-hh,or IV-ii wherein n is 0.

In another aspect, the invention provides compounds of formula IV-ii8,i.e., compound according to formula IV, wherein R₁ is CH₂CO₂H and R₂₀ is(C₀-C₆ alkyl)-OR₆.

In yet still another aspect, the invention provides compounds of formulaIV-ii9, i.e., compounds of formula IV-ii8, wherein R₆ is C₁-C₆ alkanoyl,wherein the alkyl portion of the alkanoyl group is substituted with oneor more halogens (preferably F or Cl, more preferably, F.) Or R₆ can be—(C₁-C₄ alkyl)-phenyl, —(C₁-C₄ alkanoyl)-phenyl, or phenyl, wherein thephenyl groups are optionally substituted with 1, 2, 3, 4, or 5 groupsthat are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, OH, C₁-C₄haloalkyl (such as CF₃), C₁-C₄ haloalkoxy (such as OCF₃), amino, or monoor di C₁-C₆ alkylamino.

In still yet another aspect, the invention provides compounds of formulaIV-ii10, i.e., compound according to formula IV-ii9, wherein R₂₀ is—(C₀-C₆ alkyl)-O—R₆.

In still yet another aspect, the invention provides compounds of formulaIV-ii11, i.e., compound according to formula IV-ii10, wherein R₂₀ is—(C₀-C₄ alkyl)-O—R₆.

In another aspect, the invention provides compounds of formula IV-ii12,i.e., compounds according to any one of formulas IV-ii8, IV-ii9,IV-ii10, or IV-ii11, wherein at least one of R₃₀ and R₄₀ is H.

In still yet another aspect, the invention provides compounds of formulaIV-ii13, i.e., compounds of formula IV-ii12, wherein one of R₃₀ and R₄₀is halogen (in one aspect, F or Cl), OH, amino, mono ordi(C₁-C₄)alkylamino, hydroxy(C₁-C₄)alkyl, CF₃, or OCF₃.

In yet still another aspect, the invention provides compounds of formulaIV-ii14, i.e., compounds of formula IV-ii12, wherein both R₃₀ and R₄₀are H.

In yet another aspect, the invention provides compounds of formulaIV-ii15, i.e., compounds according to any one of formulas IV-ii8,IV-ii9, IV-ii10, IV-ii11, IV-ii12, IV-ii13, or IV-ii14 wherein n is 1.

In yet still another aspect, the invention provides compounds of formulaIV-ii16, i.e., compounds of formula IV-ii15, wherein R₃ is halogen, OH,C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₂ haloalkyl, or C₁-C₂ haloalkoxy.

In still yet another aspect, the invention provides compounds of formulaIV-ii17, i.e., compounds of formula IV-ii16, wherein R₃ is halogen, OH,C₁-C₄ alkyl, C₁-C₄ alkoxy, CF₃, or OCF₃.

In still another aspect, the invention provides compounds of formulaIV-ii18, i.e., compounds of formula IV-ii17, wherein R₃ is halogen.

In yet another aspect, the invention provides compounds of formulaIV-ii19, i.e., compounds of formula IV-ii17, wherein R₃ is OH, C₁-C₄alkyl, or C₁-C₄ alkoxy.

In yet still another aspect, the invention provides compounds of formulaIV-ii20, i.e., compounds of formula IV-ii17, wherein R₃ is CF₃ or OCF₃.

In still another aspect, the invention provides compounds of formulaIV-ii21, i.e., compounds according to any one of formulas IV-ii8,IV-ii9, IV-ii10, IV-ii11, IV-ii12, IV-ii13, or IV-ii14 wherein n is 0.

In another aspect, the invention provides compounds of formula IV-jj,i.e., compounds of formula IV, wherein R₁ is H and R₃₀ is —(C₀-C₆alkyl)-COR₅.

In yet another aspect, the invention provides compounds of formulaIV-kk, i.e., compounds of formula IV-jj, wherein R₅ is C₁-C₆ alkoxyoptionally substituted with 1 or 2 groups that are independently OH,C₁-C₄ alkoxy, piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl, C₃-C₇cycloalkyl, —SO₂—(C₁-C₄ alkyl), —SO₂—(C₁-C₄ haloalkyl), or —SO₂-phenylwherein the cyclic portions of the above are optionally substituted at asubstitutable position with groups that are independently C₁-C₄ alkyl,C₁-C₄ alkoxy, halogen, OH, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, amino, ormono or dialkylamino.

In still yet another aspect, the invention provides compounds of formulaIV-ll, i.e., compounds of formula IV-kk, wherein R₅ is C₁-C₆ alkoxyoptionally substituted with 1 group that is piperidinyl, pyrrolidinyl,morpholinyl, or piperazinyl wherein the cyclic portions of the above ateoptionally substituted at a substitutable position with groups that ateindependently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, OH, C₁-C₄ haloalkyl,C₁-C₄ haloalkoxy, amino, or mono or dialkylamino.

In still another aspect, the invention provides compounds of formulaIV-nn, i.e., compounds of formula IV-kk, wherein R₅ is C₁-C₆ alkoxyoptionally substituted with 1 group that is —SO₂—(C₁-C₄ alkyl),—SO₂—(C₁-C₄ haloalkyl), or —SO₂-phenyl wherein the cyclic portions ofthe above are optionally substituted at a substitutable position withgroups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, OH,C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, amino, or mono or dialkylamino.

In another aspect, the invention provides compounds of formula IV-nn,i.e., compounds of formula IV-kk, wherein R₅ is C₁-C₆ alkoxy optionallysubstituted with C₃-C₇ cycloalkyl (preferably C₃-C₆ cycloalkyl, morepreferably C₃-C₅ cycloalkyl, still mole preferably, cyclopropyl) whereinthe cyclic portions of the above are optionally substituted at asubstitutable position with groups that are independently C₁-C₄ alkyl,C₁-C₄ alkoxy, halogen, OH, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, amino, ormono or dialkylamino.

In still another aspect, the invention provides compounds of formulaIV-oo, i.e., compounds of formula IV-jj, wherein R₅ is OH, amino, monoor dialkylamino, or C₁-C₆ haloalkoxy.

In yet another aspect, the invention provides compounds of formulaIV-pp, i.e., compounds of formula IV-oo, wherein R₅ is amino, or mono ordi(C₁-C₆ alkyl)amino.

In yet still another aspect, the invention provides compounds of formulaIV-qq, i.e., compounds of formula IV-jj, wherein R₅ is C₁-C₆ haloalkoxyoptionally substituted with 1 OH.

In yet another aspect, the invention provides compounds of formulaIV-rr, i.e., compounds of formula IV-qq, wherein R₅ is—CH₂C(halogen)₂C(halogen)₃, —CH₂CH₂C(halogen)₃, where each halogen isindependently F or Cl.

In still another aspect, the invention provides compounds of formulaIV-ss, i.e., compounds of formula IV-rr, wherein R₅ is —CH₂CF₂CF₃,—CH₂CH₂CF₃.

In another aspect, the invention provides compounds of formula IV-tt,i.e., compounds of formula IV-qq, wherein R₅ is—CH(CH₃)C(halogen)₂C(halogen)₃, —CH(CH₂halogen)₂, —CH(CH₃)C(halogen)₃,—CH(C(halogen)₃)₂, —C(CH₃)(C(halogen)₃)₂, or —CH(OH)C(halogen)₃, whereeach halogen is independently F or Cl.

In yet another aspect, the invention provides compounds of formulaIV-uu, i.e., compounds of formula IV-tt, wherein R₅ is —CH(CH₃)CF₂CF₃,—CH(CH₂F)₂, —CH(CH₃)CF₃, —CH(CF₃)₂, —C(CH₃)(CF₃)₂, or —CH(OH)CF₃.

In still another aspect, the invention provides compounds of formulaIV-vv, i.e., compounds of formula IV-tt, wherein R₅ is—C(CH₃)(C(halogen)₃)₂ preferably each halogen is F.

In still yet another aspect, the invention provides compounds of formulaIV-ww, i.e., compounds of formula IV-tt, wherein R₅ is—CH(OH)C(halogen)₃. In one case, the stereogenic center in R₅ has theS-configuration. In another case, the stereogenic center in R₅ has theR-configuration.

In another aspect, the invention provides compounds of formula IV-xx,i.e., compounds according to any one of formulas IV-jj, IV-kk, IV-ll,IV-mm, IV-nn, IV-oo, IV-pp, IV-qq, IV-rr, IV-ss, IV-tt, IV-uu, IV-vv, orIV-ww, wherein at least one of R₂₀ and R₄₀ is H.

In still yet another aspect, the invention provides compounds of formulaIV-yy, i.e., compounds of formula IV-xx, wherein one of R₂₀ and R₄₀ ishalogen (in one aspect, F or Cl), OH, amino, mono ordi(C₁-C₄)alkylamino, hydroxy(C₁-C₄)alkyl, CF₃, or OCF₃.

In yet still another aspect, the invention provides compounds of formulaIV-zz, i.e., compounds of formula IV-xx, wherein both R₂₀ and R₄₀ are H.

In yet another aspect, the invention provides compounds of formulaIV-zz1, i.e., compounds according to any one of formulas IV-xx, IV-yy,or IV-zz wherein n is 1.

In yet still another aspect, the invention provides compounds of formulaIV-zz2, i.e., compounds of formula IV-zz1, wherein R₃ is halogen, OH,C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₂ haloalkyl, or C₁-C₂ haloalkoxy.

In still yet another aspect, the invention provides compounds of formulaIV-zz3, i.e., compounds of formula IV-zz2, wherein R₃ is halogen, OH,C₁-C₄ alkyl, C₁-C₄ alkoxy, CF₃, or OCF₃.

In still another aspect, the invention provides compounds of formulaIV-zz4, i.e., compounds of formula IV-zz3, wherein R₃ is halogen.

In yet another aspect, the invention provides compounds of formulaIV-zz5, i.e., compounds of formula IV-zz3, wherein R₃ is OH, C₁-C₄alkyl, or C₁-C₄ alkoxy.

In yet still another aspect, the invention provides compounds of formulaIV-zz6, i.e., compounds of formula IV-zz3, wherein R₃ is CF₃ or OCF₃.

In still another aspect, the invention provides compounds of formulaIV-zz7, i.e., compounds according to any one of formulas IV-xx, IV-yy,or IV-zz wherein n is 0.

In another aspect, the invention provides compounds of formula IV-zz8,i.e., compound according to formula IV, wherein R₁ is H and R₃₀ is(C₀-C₆ alkyl)-OR₆.

In yet still another aspect, the invention provides compounds of formulaIV-zz9, i.e., compounds of formula IV-zz8, wherein R₆ is C₁-C₆ alkanoyl,wherein the alkyl portion of the alkanoyl group is substituted with oneor more halogens (preferably F or Cl, more preferably, F.) Or R₆ can be—(C₁-C₄ alkyl)-phenyl, —(C₁-C₄ alkanoyl)-phenyl, or phenyl, wherein thephenyl groups are optionally substituted with 1, 2, 3, 4, or 5 groupsthat are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, OH, C₁-C₄haloalkyl (such as CF₃), C₁-C₄ haloalkoxy (such as OCF₃), amino, or monoor di C₁-C₆ alkylamino.

In still yet another aspect, the invention provides compounds of formulaIV-zz10, i.e., compound according to formula IV-zz9, wherein R₃₀ is—(C₀-C₆ alkyl)-O—R₆.

In still yet another aspect, the invention provides compounds of formulaIV-zz11, i.e., compound according to formula IV-zz10, wherein R₃₀ is—(C₀-C₄ alkyl)-O—R₆.

In another aspect, the invention provides compounds of formula IV-zz12,i.e., compounds according to any one of formulas IV-zz8, IV-zz9,IV-zz10, or IV-zz11, wherein at least one of R₂₀ and R₄₀ is H.

In still yet another aspect, the invention provides compounds of formulaIV-zz13, i.e., compounds of formula IV-zz12, wherein one of R₂₀ and R₄₀is halogen (in one aspect, F or Cl), OH, amino, mono ordi(C₁-C₄)alkylamino, hydroxy(C₁-C₄)alkyl, CF₃, or OCF₃.

In yet still another aspect, the invention provides compounds of formulaIV-zz14, i.e., compounds of formula IV-zz12, wherein both R₂₀ and R₄₀are H.

In yet another aspect, the invention provides compounds of formulaIV-zz15, i.e., compounds according to any one of formulas IV-zz8,IV-zz9, IV-z10, IV-zz11, IV-zz12, IV-zz13, or IV-zz14 wherein n is 1.

In yet still another aspect, the invention provides compounds of formulaIV-zz16, i.e., compounds of formula IV-zz15, wherein R₃ is halogen, OH,C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₂ haloalkyl, or C₁-C₂ haloalkoxy.

In still yet another aspect, the invention provides compounds of formulaIV-zz17, i.e., compounds of formula IV-zz16, wherein R₃ is halogen, OH,C₁-C₄ alkyl, C₁-C₄ alkoxy, CF₃, or OCF_(3.)

In still another aspect, the invention provides compounds of formulaIV-zz18, i.e., compounds of formula IV-zz17, wherein R₃ is halogen.

In yet another aspect, the invention provides compounds of formulaIV-zz19, i.e., compounds of formula IV-zz17, wherein R₃ is OH, C₁-C₄alkyl, or C₁-C₄ alkoxy.

In yet still another aspect, the invention provides compounds of formulaIV-zz20 , i.e., compounds of formula IV-zz17, wherein R₃ is CH₃ or OCF₃.

In still another aspect, the invention provides compounds of formulaIV-zz21, i.e., compounds according to any one of formulas IV-zz8,IV-zz9, IV-zz10, IV-zz11, IV-zz12, IV-zz13, or IV-zz14 wherein n is 0.

In another aspect, the invention provides compounds of formula IV-aaa,i.e., compounds of formula IV, wherein R₁ is CH₂COOH and R₃₀ is —(C₀-C₆alkyl-COR₅.

In yet another aspect, the invention provides compounds of formulaIV-bbb, i.e., compounds of formula IV-aaa, wherein R₅ is C₁-C₆ alkoxyoptionally substituted with 1 or 2 groups that are independently OH,C₁-C₄ alkoxy, piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl, C₃-C₇cycloalkyl, —SO₂—(C₁-C₄ alkyl), —SO₂—(C₁-C₄ haloalkyl), or —SO₂-phenylwherein the cyclic portions of the above are optionally substituted at asubstitutable position with groups that are independently C₁-C₄ alkyl,C₁-C₄ alkoxy, halogen, OH, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, amino, ormono or dialkylamino.

In still yet another aspect, the invention provides compounds of formulaIV-ccc, i.e., compounds of formula IV-bbb, wherein R₅ is C₁-C₆ alkoxyoptionally substituted with 1 group that is piperidinyl, pyrrolidinyl,morpholinyl, or piperazinyl wherein the cyclic portions of the above areoptionally substituted at a substitutable position with groups that areindependently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, OH, C₁-C₄ haloalkyl,C₁-C₄ haloalkoxy, amino, or mono or dialkylamino.

In still another aspect, the invention provides compounds of formulaIV-ddd, i.e., compounds of formula IV-bbb, wherein R₅ is C₁-C₆ alkoxyoptionally substituted with 1 group that is —SO₂—(C₁-C₄ alkyl),—SO₂—(C₁-C₄ haloalkyl), or —SO₂-phenyl wherein the cyclic portions ofthe above are optionally substituted at a substitutable position withgroups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, OH,C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, amino, or mono or dialkylamino.

In another aspect, the invention provides compounds of formula IV-eee,i.e., compounds of formula IV-bbb, wherein R₅ is C₁-C₆ alkoxy optionallysubstituted with C₃-C₇ cycloalkyl (preferably C₃-C₆ cycloalkyl, morepreferably C₃-C₅ cycloalkyl, still more preferably, cyclopropyl) whereinthe cyclic portions of the above are optionally substituted at asubstitutable position with groups that are independently C₁-C₄ alkyl,C₁-C₄ alkoxy, halogen, OH, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, amino, ormono or dialkylamino.

In still another aspect, the invention provides compounds of formulaIV-fff, i.e., compounds of formula IV-aaa, wherein R₅ is OH, amino, monoor dialkylamino, or C₁-C₆ haloalkoxy.

In yet another aspect, the invention provides compounds of formulaIV-ggg, i.e., compounds of formula IV-fff, wherein R₅ is amino, or monoor di(C₁-C₆ alkyl)amino.

In yet still another aspect, the invention provides compounds of formulaIV-hhh, i.e., compounds of formula IV-aaa, wherein R₅ is C₁-C₆haloalkoxy optionally substituted with 1 OH.

In yet another aspect, the invention provides compounds of formulaIV-iii, i.e., compounds of formula IV-hhh, wherein R₅ is—CH₂C(halogen)₂C(halogen)₃, —CH₂CH₂C(halogen)₃, where each halogen isindependently F or Cl.

In still another aspect, the invention provides compounds of formulaIV-jjj, i.e., compounds of formula IV-iii, wherein R₅ is —CH₂CF₂F₃,—CH₂CH₂CF₃.

In another aspect, the invention provides compounds of formula IV-kkk,i.e., compounds of formula IV-hhh, wherein R₅ is—CH(CH₃)C(halogen)₂C(halogen)₃, —CH(CH₂halogen)₂, —CH(CH₃)C(halogen)₃,—CH(C(halogen)₃)₂, —C(CH₃)(C(halogen)₃)₂, or —CH(OH)C(halogen)₃, whereeach halogen is independently F or Cl.

In yet another aspect, the invention provides compounds of formulaIV-lll, i.e., compounds of formula IV-kkk, wherein R₅ is —CH(CH₃)CF₂CF₃,—CH(CH₂F)₂, —CH(CH₃)CF₃, —CH(CF₃)₂, —C(CH₃)(CF₃)₂, or —CH(OH)CF₃.

In still another aspect, the invention provides compounds of formulaIV-mmm, i.e., compounds of formula IV-kkk wherein R₅ is—C(CH₃)(C(halogen)₃)₂ preferably each halogen is F.

In still yet another aspect, the invention provides compounds of formulaIV-nnn, i.e., compounds of formula IV-kkk, wherein R₅ is—CH(OH)C(halogen)₃. In one case, the stereogenic center in R₅ has theS-configuration. In another case, the stereogenic center in R₅ has theR-configuration.

In another aspect, the invention provides compounds of formula IV-ooo,i.e., compounds according to any one of formulas IV-aaa, IV-bbb, IV-ccc,IV-ddd, IV-eee, IV-fff, IV-ggg, IV-hhh, IV-iii, IV-jjj, IV-kkk, IV-lll,IV-mmm, or IV-nnn, wherein at least one of R₂₀ , and R₄₀ is H.

In still yet another aspect, the invention provides compounds of formulaIV-ppp, i.e., compounds of formula IV-ooo, wherein one of R₂₀ and R₄₀ ishalogen (in one aspect, F or Cl), OH, amino, mono ordi(C₁-C₄)alkylamino, hydroxy(C₁-C₄)alkyl, CF₃, or OCF₃.

In yet still another aspect, the invention provides compounds of formulaIV-qqq, i.e., compounds of formula IV-ooo, wherein both R₂₀ and R₄₀ areH.

In yet another aspect, the invention provides compounds of formulaIV-rrr, i.e., compounds according to any one of formulas IV-ooo, IV-ppp,or IV-qqq wherein n is 1.

In yet still another aspect, the invention provides compounds of formulaIV-sss, i.e., compounds of formula IV-rrr, wherein R₃ is halogen, OH,C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₂ haloalkyl, or C₁-C₂ haloalkoxy.

In still yet another aspect, the invention provides compounds of formulaIV-ttt, i.e., compounds of formula IV-sss, wherein R₃ is halogen, OH,C₁-C₄ alkyl, C₁-C₄ alkoxy, CF₃, or OCF₃.

In still another aspect, the invention provides compounds of formulaIV-uuu, i.e., compounds of formula IV-ttt, wherein R₃ is halogen.

In yet another aspect, the invention provides compounds of formulaIV-vvv, i.e., compounds of formula IV-ttt, wherein R₃ is OH, C₁-C₄alkyl, or C₁-C₄ alkoxy.

In yet still another aspect, the invention provides compounds of formulaIV-www, i.e., compounds of formula IV-ttt, wherein R₃ is CF₃ or OCF₃.

In still another aspect, the invention provides compounds of formulaIV-xxx, i.e., compounds according to any one of formulas IV-ooo, IV-ppp,or IV-qqq wherein n is 0.

In another aspect, the invention provides compounds of formula IV-xxx1,i.e., compound according to formula IV, wherein R₁ is CH₂CO₂H and R₃₀ is(C₀-C₆ alkyl)-OR₆.

In yet still another aspect, the invention provides compounds of formulaIV-xxx2, i.e., compounds of formula IV-xxx1, wherein R₆ is C₁-C₆alkanoyl, wherein the alkyl portion of the alkanoyl group is substitutedwith one or more halogens (preferably F or Cl, more preferably, F.) OrR₆ can be —(C₁-C₄ alkyl)-phenyl, —(C₁-C₄ alkanoyl)-phenyl, or phenyl,wherein the phenyl groups are optionally substituted with 1, 2, 3, 4, or5 groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, OH,C₁-C₄ haloalkyl (such as CF₃), C₁-C₄ haloalkoxy (such as OCF₃), amino,or mono or di C₁-C₆ alkylamino.

In still yet another aspect, the invention provides compounds of formulaIV-xxx3, i.e., compound according to formula IV-xxx2, wherein R₃₀ is—(C₀-C₆ alkyl)-O—R₆.

In still yet another aspect, the invention provides compounds of formulaIV-xxx4, i.e., compound according to formula IV-xxx3, wherein R₃₀ is—(C₀-C₄ alkyl)-O—R₆.

In another aspect, the invention provides compounds of formula IV-xxx5,i.e., compounds according to any one of formulas IV-xxx1, IV-xxx2,IV-xxx3, or IV-xxx4, wherein at least one of R₂₀ and R₄₀ is H.

In still yet another aspect, the invention provides compounds of formulaIV-xxx6, i.e., compounds of formula IV-xxx5, wherein one of R₂₀ and R₄₀is halogen (in one aspect, F or Cl), OH, amino, mono ordi(C₁-C₄)alkylamino, hydroxy(C₁-C₄)alkyl, CF₃, or OCF₃.

In yet still another aspect, the invention provides compounds of formulaIV-xxx7, i.e., compounds of formula IV-xxx5, wherein both R₂₀ and R₄₀are H.

In yet another aspect, the invention provides compounds of formulaIV-xxx8, i.e., compounds according to any one of formulas IV-xxx1,IV-xxx2, IV-xxx3, IV-xxx11, IV-xxx4, IV-xxx5, or IV-xxx6 wherein n is 1.

In yet still another aspect, the invention provides compounds of formulaIV-xxx9, i.e., compounds of formula IV-xxx8, wherein R₃ is halogen, OH,C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₂ haloalkyl, or C₁-C₂ haloalkoxy.

In still yet another aspect, the invention provides compounds of formulaIV-xxx10, i.e., compounds of formula IV-xxx9, wherein R₃ is halogen, OH,C₁-C₄ alkyl, C₁-C₄ alkoxy, CF₃, or OCF₃.

In still another aspect, the invention provides compounds of formulaIV-xxx11, i.e., compounds of formula IV-xxx10, wherein R₃ is halogen.

In yet another aspect, the invention provides compounds of formulaIV-xxx12, i.e., compounds of formula IV-xxx10, wherein R₃ is OH, C₁-C₄alkyl, or C₁-C₄ alkoxy.

In yet still another aspect, the invention provides compounds of formulaIV-xxx13, i.e., compounds of formula IV-xxx10, wherein R₃ is CF₃ orOCF₃.

In still another aspect, the invention provides compounds of formulaIV-xxx14, i.e., compounds according to any one of formulas IV-xxx1,IV-xxx2, IV-xxx3, IV-xxx4, IV-xxx5, IV-xxx6, or IV-xxx7 wherein n is 0.

In another aspect, the invention provides compounds of formula V, i.e.,compounds of formula I, where Ar is an optionally substituted naphthylgroup of the formula:

wherein:

-   n is 0, 1, or 2;-   p is 1 or 2;-   R₁ is H or CH₂COOH;-   R₃ at each occurrence is independently halogen, OH, C₁-C₆ alkyl,    C₁-C₆ alkoxy, C₁-C₄ haloalkyl, or C₁-C₄ haloalkoxy; and-   R₂₀, R₃₀, R₄₀, and R₈₀ are independently H, —(C₀-C₆ alkyl)-COR₅,    —(C₁-C₆ alkyl)-COR₅, (C₀-C₆ alkyl)-O—R₆, halogen, OH, amino, mono or    dialkylamino, hydroxyalkyl, C₁-C₄ haloalkyl, or C₁-C₄ haloalkoxy,    wherein    -   R₅ is C₁-C₆ alkoxy optionally substituted with 1 or 2 groups        that are independently OH, C₁-C₄ alkoxy, piperidinyl,        pyrrolidinyl, morpholinyl, piperazinyl, C₃-C₇ cycloalkyl,        —SO₂—(C₁-C₄ alkyl), —SO₂—(C₁-C₄ haloalkyl), or —SO₂-phenyl, OH,        amino, mono or dialkylamino, or C₁-C₆ haloalkoxy optionally        substituted with 1 OH, wherein the cyclic portions of the above        are optionally substituted at a substitutable position with        groups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy,        halogen, OH, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, amino, or mono        or dialkylamino;    -   and    -   R₆ is C₁-C₆ alkanoyl, phenyl C₁-C₆ alkanoyl, (C₁-C₆        alkyl)-O-phenyl, or phenyl, wherein the phenyl groups are        optionally substituted with 1, 2, 3, 4, or 5 groups that are        independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, OH, C₁-C₄        haloalkyl, C₁-C₄ haloalkoxy, amino, or mono or dialkylamino.

In another aspect, the invention provides compounds of formula V-a,i.e., compounds of formula V, wherein R₁ is H.

In still another aspect, the invention provides compounds of formulaV-b, i.e., compounds of formula V-a, wherein R₂₀ is —(C₀-C₆ alkyl)-COR₅.

In yet another aspect, the invention provides compounds of formula V-c,i.e., compounds of formula V-b, wherein R₅ is C₁-C₆ alkoxy optionallysubstituted with 1 or 2 groups that are independently OH, C₁-C₄ alkoxy,piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl, C₃-C₇ cycloalkyl,—SO₂—(C₁-C₄ alkyl), —SO₂—(C₁-C₄ haloalkyl), or —SO₂-phenyl wherein thecyclic portions of the above are optionally substituted at asubstitutable position with groups that are independently C₁-C₄ alkyl,C₁-C₄ alkoxy, halogen, OH, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, amino, ormono or dialkylamino.

In still yet another aspect, the invention provides compounds of formulaV-d, i.e., compounds of formula V-c, wherein R₅ is C₁-C₆ alkoxyoptionally substituted with 1 group that is piperidinyl, pyrrolidinyl,morpholinyl, or piperazinyl wherein the cyclic portions of the above areoptionally substituted at a substitutable position with groups that areindependently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, OH, C₁-C₄ haloalkyl,C₁-C₄ haloalkoxy, amino, or mono or dialkylamino.

In still another aspect, the invention provides compounds of formulaV-e, i.e., compounds of formula V-c, wherein R₅ is C₁-C₆ alkoxyoptionally substituted with 1 group that is —SO₂—(C₁-C₄ alkyl),—SO₂—(C₁-C₄ haloalkyl), or —SO₂-phenyl wherein the cyclic portions ofthe above are optionally substituted at a substitutable position withgroups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, OH,C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, amino, or mono or dialkylamino.

In another aspect, the invention provides compounds of formula V-f,i.e., compounds of formula V-c, wherein R₅ is C₁-C₆ alkoxy optionallysubstituted with C₃-C₇ cycloalkyl (preferably C₃-C₆ cycloalkyl, morepreferably C₃-C₅ cycloalkyl, still more preferably, cyclopropyl) whereinthe cyclic portions of the above are optionally substituted at asubstitutable position with groups that are independently C₁-C₄ alkyl,C₁-C₄ alkoxy, halogen, OH, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, amino, ormono or dialkylamino.

In still another aspect, the invention provides compounds of formulaV-g, i.e., compounds of formula V-b, wherein R₅ is OH, amino, mono ordialkylamino, or C₁-C₆ haloalkoxy.

In yet another aspect, the invention provides compounds of formula V-h,i.e., compounds of formula V-g, wherein R₅ is amino, or mono or di(C₁-C₆alkyl)amino.

In yet still another aspect, the invention provides compounds of formulaV-i, i.e., compounds of formula V-b, wherein R₅ is C₁-C₆ haloalkoxyoptionally substituted with 1 OH.

In yet another aspect, the invention provides compounds of formula V-j,i.e., compounds of formula V-i, wherein R₅ is—CH₂C(halogen)₂C(halogen)₃, —CH₂CH₂C(halogen)₃, where each halogen isindependently F or Cl.

In still another aspect, the invention provides compounds of formulaV-k, i.e., compounds of formula V-j, wherein R₅ is —CH₂CF₂CF₃,—CH₂CH₂CF₃.

In another aspect, the invention provides compounds of formula V-l,i.e., compounds of formula V-i, wherein R₅ is—CH(CH₃)C(halogen)₂C(halogen)₃, —CH(CH₂halogen)₂, —CH(CH₃)C(halogen)₃,—CH(C(halogen)₃)₂, —C(CH₃)(C(halogen)₃)₂, or —CH(OH)C(halogen)₃, whereeach halogen is independently F or Cl.

In yet another aspect, the invention provides compounds of formula V-l1,i.e., compounds of formula V-i, wherein R₅ is —CH(CH₃)CF₂CF₃,—CH(CH₂F)₂, —CH(CH₃)CF₃, —CH(CF₃)₂, —C(CH₃)(CF₃)₂, or —CH(OH)CF₃.

In still another aspect, the invention provides compounds of formulaV-m, i.e., compounds of formula V-l, wherein R₅ is —C(CH₃)(C(halogen)₃)₂preferably each halogen is F.

In still yet another aspect, the invention provides compounds of formulaV-n, i.e., compounds of formula V-l, wherein R₅ is —CH(OH)C(halogen)₃.In one case, the stereogenic center in R₅ has the S-configuration, Inanother case, the stereogenic center in R₅ has the R-configuration.

In another aspect, the invention provides compounds of formula V-o,i.e., compounds according to any one of formulas V-a, V-b, V-c, V-d,V-e, V-f, V-g, V-h, V-I, V-j, V-k, V-l, V-l, V-m, or V-n, wherein atleast one of R₃₀ and R₄₀ is H; and R₈₀ is H, Cl, or OCF₃.

In still yet another aspect, the invention provides compounds of formulaV-p, i.e., compounds of formula V-o, wherein one of R₃₀ and R₄₀ ishalogen (in one aspect, F or Cl), OH, amino, mono ordi(C₁-C₄)alkylamino, hydroxy(C₁-C₄)alkyl, CF₃, or OCF₃.

In yet still another aspect, the invention provides compounds of formulaV-q, i.e., compounds of formula V-o, wherein both R₃₀ and R₄₀ are H.

In yet another aspect, the invention provides compounds of formula V-q1,i.e., compounds according to any one of formulas V-o, V-p, or V-qwherein n is 1.

In yet still another aspect, the invention provides compounds of formulaV-q2, i.e., compounds of formula V-q1, wherein R₃ is halogen, OH, C₁-C₄,alkyl, C₁-C₄ alkoxy, C₁-C₂ haloalkyl, or C₁-C₂ haloalkoxy.

In still yet another aspect, the invention provides compounds of formulaV-q3, i.e., compounds of formula V-q2, wherein R₃ is halogen, OH, C₁-C₄alkyl, C₁-C₄ alkoxy, CF₃, or OCF₃.

In still another aspect, the invention provides compounds of formulaV-q4, i.e., compounds of formula V-q3, wherein R₃ is halogen.

In yet another aspect, the invention provides compounds of formula V-q5,i.e., compounds of formula V-q3, wherein R₃ is OH, C₁-C₄ alkyl, or C₁-C₄alkoxy.

In yet still another aspect, the invention provides compounds of formulaV-q6, i.e., compounds of formula V-q3, wherein R₃ is CF₃ or OCF₃.

In still another aspect, the invention provides compounds of formulaV-q7, i.e., compounds according to any one of formulas V-o, V-p, or V-qwherein n is 0.

In another aspect, the invention provides compounds of formula V-q8,i.e., compound according to formula V-a, wherein R₂₀ is —(C₀-C₆alkyl)-O—R₆.

In yet still another aspect, the invention provides compounds of formulaV-q9, i.e., compounds of formula V-q8, wherein R₆ is C₁-C₆ alkanoyl,wherein the alkyl portion of the alkanoyl group is substituted with oneor more halogens (preferably F or Cl, more preferably, F.) Or R₆ can be—(C₁-C₄ alkyl)-phenyl, —(C₁-C₄ alkanoyl)-phenyl, or phenyl, wherein thephenyl groups are optionally substituted with 1, 2, 3, 4, or 5 groupsthat are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, OH, C₁-C₄haloalkyl (such as CF₃), C₁-C₄ haloalkoxy (such as OCF₃), amino, or monoor di C₁-C₆ alkylamino.

In still yet another aspect, the invention provides compounds of formulaV-q10, i.e., compound according to formula V-q9, wherein R₂₀ is —(C₀-C₆alkyl)-O—R₆.

In still yet another aspect, the invention provides compounds of formulaV-q11, i.e., compound according to formula V-q10, wherein R₂₀ is —(C₀-C₄alkyl)-O—R₆.

In another aspect, the invention provides compounds of formula V-q12,i.e., compounds according to any one of formulas V-q8, V-g9, V-q10, orV-q11, wherein at least one of R₃₀ and R₄₀ is H; and R₈₀ is H, Cl, orOCF₃.

In still yet another aspect, the invention provides compounds of formulaV-q13, i.e., compounds of formula V-q12, wherein one of R₃₀ and R₄₀ ishalogen (in one aspect, F or Cl), OH, amino, mono ordi(C₁-C₄)alkylamino, hydroxy(C₁-C₄)alkyl, CF₃, or OCF₃.

In yet still another aspect, the invention provides compounds of formulaV-q14, i.e., compounds of formula V-q12, wherein both R₃₀ and R₄₀ are H.

In yet another aspect, the invention provides compounds of formulaV-q15, i.e., compounds according to any one of formulas V-q8, V-q9,V-q10, V-q11, V-q12, V-q13, or V-q14 wherein n is 1.

In yet still another aspect, the invention provides compounds of formulaV-q16, i.e., compounds of formula V-q15, wherein R₃ is halogen, OH,C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₂ haloalkyl, or C₁-C₂ haloalkoxy.

In still yet another aspect, the invention provides compounds of formulaV-q17, i.e., compounds of formula V-q16, wherein R₃ is halogen, OH,C₁-C₄ alkyl, C₁-C₄ alkoxy, CF₃, or OCF₃.

In still another aspect, the invention provides compounds of formulaV-q18, i.e., compounds of formula V-q17, wherein R₃ is halogen.

In yet another aspect, the invention provides compounds of formulaV-q19, i.e., compounds of formula V-q17, wherein R₃ is OH, C₁-C₄ alkyl,or C₁-C₄ alkoxy.

In yet still another aspect, the invention provides compounds of formulaV-q20, i.e., compounds of formula V-q17, wherein R₃ is CF₃ or OCF₃.

In still another aspect, the invention provides compounds of formulaV-q21, i.e., compounds according to any one of formulas V-q8, V-q9,V-q10, V-q11, V-q12, V-q13, or V-q14 wherein n is 0.

In another aspect, the invention provides compounds of formula V-r,i.e., compounds of formula V, wherein R₁ is CH₂COOH.

In still another aspect, the invention provides compounds of formulaV-s, i.e., compounds of formula V-r, wherein R₂₀ is —(C₀-C₆ alkyl)-COR₅.

In yet another aspect, the invention provides compounds of formula V-t,i.e., compounds of formula V-s, wherein R₅ is C₁-C₆ alkoxy optionallysubstituted with 1 or 2 groups that are independently OH, C₁-C₄ alkoxy,piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl, C₃-C₇ cycloalkyl,—SO₂—(C₁-C₄ alkyl), —SO₂—(C₁-C₄ haloalkyl), or —SO₂-phenyl wherein thecyclic portions of the above are optionally substituted at asubstitutable position with groups that are independently C₁-C₄ alkyl,C₁-C₄ alkoxy, halogen, OH, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, amino, ormono or dialkylamino.

In still yet another aspect, the invention provides compounds of formulaV-u, i.e., compounds of formula V-t, wherein R₅ is C₁-C₆ alkoxyoptionally substituted with 1 group that is piperidinyl, pyrrolidinyl,morpholinyl, or piperazinyl wherein the cyclic portions of the above areoptionally substituted at a substitutable position with groups that areindependently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, OH, C₁-C₄ haloalkyl,C₁-C₄ haloalkoxy, amino, or mono or dialkylamino.

In still another aspect, the invention provides compounds of formulaV-v, i.e., compounds of formula V-t, wherein R₅ is C₁-C₆ alkoxyoptionally substituted with 1 group that is —SO₂—(C₁-C₄ alkyl),—SO₂—(C₁-C₄ haloalkyl), or —SO₂-phenyl wherein the cyclic portions ofthe above are optionally substituted at a substitutable position withgroups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, OH,C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, amino, or mono or dialkylamino.

In another aspect, the invention provides compounds of formula V-w,i.e., compounds of formula V-t, wherein R₅ is C₁-C₆ alkoxy optionallysubstituted with C₃-C₇ cycloalkyl (preferably C₃-C₆ cycloalkyl, morepreferably C₃-C₅ cycloalkyl, still more preferably, cyclopropyl) whereinthe cyclic portions of the above are optionally substituted at asubstitutable position with groups that are independently C₁-C₄ alkyl,C₁-C₄ alkoxy, halogen, OH, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, amino, ofmono or dialkylamino.

In still another aspect, the invention provides compounds of formulaV-x, i.e., compounds of formula V-s, wherein R₅ is OH, amino, mono ordialkylamino, or C₁-C₆ haloalkoxy.

In yet another aspect, the invention provides compounds of formula V-y,i.e., compounds of formula V-x, wherein R₅ is amino, or mono or di(C₁-C₆alkyl)amino.

In yet still another aspect, the invention provides compounds of formulaV-z, i.e., compounds of formula V-s, wherein R₅ is C₁-C₆ haloalkoxyoptionally substituted with 1 OH.

In yet another aspect, the invention provides compounds of formula V-aa,i.e., compounds of formula V-z, wherein R₅ is—CH₂C(halogen)₂C(halogen)₃, —CH₂CH₂C(halogen)₃, where each halogen isindependently F or Cl.

In still another aspect, the invention provides compounds of formulaV-bb, i.e., compounds of formula V-aa, wherein R₅ is —CH₂CF₂CF₃,—CH₂CH₂CF₃.

In another aspect, the invention provides compounds of formula V-cc,i.e., compounds of formula V-z, wherein R₅ is—CH(CH₃)C(halogen)₂C(halogen)₃, —CH(CH₂halogen)₂, —CH(CH₃)C(halogen)₃,—CH(C(halogen)₃)₂, —C(CH₃)(C(halogen)₃)₂, or —CH(OH)C(halogen)₃, whereeach halogen is independently F or Cl.

In yet another aspect, the invention provides compounds of formula V-dd,i.e., compounds of formula V-cc, wherein R₅ is —CH(CH₃)CF₂CF₃,—CH(CH₂F)₂, —CH(CH₃)CF₃, —CH(CF₃)₂, —C(CH₃)(CF₃)₂, or —CH(OH)CF₃.

In still another aspect, the invention provides compounds of formulaV-ee, i.e., compounds of formula V-cc wherein R₅ is—C(CH₃)(C(halogen)₃)₂ preferably each halogen is F.

In still yet another aspect, the invention provides compounds of formulaV-ff, i.e., compounds of formula V-cc, wherein R₅ is —CH(OH)C(halogen)₃.In one case, the stereogenic center in R₅ has the S-configuration. Inanother case, the stereogenic center in R₅ has the R-configuration.

In another aspect, the invention provides compounds of formula V-gg,i.e., compounds according to any one of formulas V-r, V-s, V-t, V-u,V-v, V-w, V-x, V-y, V-z, V-aa, V-bb, V-cc, V-dd, V-ee, or V-ff, whereinat least one of R₃₀ and R₄₀ is H; and R₈₀ is H, Cl, or OCF₃.

In still yet another aspect, the invention provides compounds of formulaV-hh, i.e., compounds of formula V-gg, wherein one of R₃₀ and R₄₀ ishalogen (in one aspect, F or Cl), OH, amino, mono ordi(C₁-C₄)alkylamino, hydroxy(C₁-C₄)alkyl, CF₃, or OCF₃.

In yet still another aspect, the invention provides compounds of formulaV-ii, i.e., compounds of formula V-gg, wherein both R₃₀ and R₄₀ are H.

In yet another aspect, the invention provides compounds of formulaV-ii1, i.e., compounds according to any one of formulas V-gg, V-hh, orV-ii wherein n is 1.

In yet still another aspect, the invention provides compounds of formulaV-ii2, i.e., compounds of formula V-ii1, wherein R₃ is halogen, OH,C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₂ haloalkyl, or C₁-C₂ haloalkoxy.

In still yet another aspect, the invention provides compounds of formulaV-ii3, i.e., compounds of formula V-ii2, wherein R₃ is halogen, OH,C₁-C₄ alkyl, C₁-C₄ alkoxy, CF₃, or OCF₃.

In still another aspect, the invention provides compounds of formulaV-ii4, i.e., compounds of formula V-ii3, wherein R₃ is halogen.

In yet another aspect, the invention provides compounds of formulaV-ii5, i.e., compounds of formula V-ii2, wherein R₃ is OH, C₁-C₄ alkyl,or C₁-C₄ alkoxy.

In yet still another aspect, the invention provides compounds of formulaV-ii6, i.e., compounds of formula V-ii2, wherein 1R₃ is CF₃ or OCF₃.

In still another aspect, the invention provides compounds of formulaV-ii7, i.e., compounds according to any one of formulas V-gg, V-hh, orV-ii wherein n is 0.

In another aspect, the invention provides compounds of formula V-ii8,i.e., compound according to formula V, wherein R₁ is CH₂CO₂H and R₂₀ is—(C₀-C₆ alkyl)-O—R₆.

In yet still another aspect, the invention provides compounds of formulaV-ii9, i.e., compounds of formula V-ii8, wherein R₆ is C₁-C₆ alkanoyl,wherein the alkyl portion of the alkanoyl group is substituted with oneor more halogens (preferably F or Cl, more preferably, F.) Or R₆ can be—(C₁-C₄ alkyl)-phenyl, —(C₁-C₄ alkanoyl)-phenyl, or phenyl, wherein thephenyl groups are optionally substituted with 1, 2, 3, 4, or 5 groupsthat are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, OH, C₁-C₄haloalkyl (such as CF₃), C₁-C₄ haloalkoxy (such as OCF₃), amino, or monoor di C₁-C₆ alkylamino.

In still yet another aspect, the invention provides compounds of formulaV-ii10, i.e., compound according to formula V-ii9, wherein R₂₀ is—(C₀-C₆ alkyl)-O—R₆.

In still yet another aspect, the invention provides compounds of formulaV-ii11, i.e., compound according to formula V-ii10, wherein R₂₀ is—(C₀-C₄ alkyl)-O—R₆.

In another aspect, the invention provides compounds of formula V-ii12,i.e., compounds according to any one of formulas V-ii8, V-ii9, V-ii10,or V-ii11, wherein at least one of R₃₀ and R₄₀ is H; and R₈₀ is H, Cl,or OCF₃.

In still yet another aspect, the invention provides compounds of formulaV-ii13, i.e., compounds of formula V-ii12, wherein one of R₃₀ and R₄₀ ishalogen (in one aspect, F or Cl), OH, amino, mono ordi(C₁-C₄)alkylamino, hydroxy(C₁-C₄)alkyl, CF₃, or OCF₃.

In yet still another aspect, the invention provides compounds of formulaV-ii14, i.e., compounds of formula V-ii12, wherein both R₃₀ and R₄₀ areH.

In yet another aspect, the invention provides compounds of formulaV-ii15, i.e., compounds according to any one of formulas V-ii8, V-ii9,V-ii10, V-ii11, V-ii12, V-ii13, or V-ii14 wherein n is 1.

In yet still another aspect, the invention provides compounds of formulaV-ii16, i.e., compounds of formula V-ii15, wherein R₃ is halogen, OH,C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₂ haloalkyl, or C₁-C₂ haloalkoxy.

In still yet another aspect, the invention provides compounds of formulaV-ii17, i.e., compounds of formula V-ii16, wherein R₃ is halogen, OH,C₁-C₄ alkyl, C₁-C₄ alkoxy, CF₃, or OCF₃.

In still another aspect, the invention provides compounds of formulaV-ii18, i.e., compounds of formula V-ii17, wherein R₃ is halogen.

In yet another aspect, the invention provides compounds of formulaV-ii19, i.e., compounds of formula V-ii17, wherein R₃ is OH, C₁-C₄alkyl, or C₁-C₄ alkoxy.

In yet still another aspect, the invention provides compounds of formulaV-ii20, i.e., compounds of formula V-ii17, wherein R₃ is CF₃ or OCF₃.

In still another aspect, the invention provides compounds of formulaV-ii21, i.e., compounds according to any one of formulas V-ii8, V-ii9,V-ii10, V-ii11, V-ii12, V-ii13, or V-ii14 wherein n is 0.

In another aspect, the invention provides compounds of formula V-jj,i.e., compounds of formula V, wherein R₁ is H and R₃₀ is —(C₀-C₆alkyl)-COR₅.

In yet another aspect, the invention provides compounds of formula V-kk,i.e., compounds of formula V-jj, wherein R₅ is C₁-C₆ alkoxy optionallysubstituted with 1 or 2 groups that are independently OH, C₁-C₄ alkoxy,piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl, C₃-C₇ cycloalkyl,—SO₂—(C₁-C₄ alkyl), —SO₂—(C₁-C₄ haloalkyl), or —SO₂-phenyl wherein thecyclic portions of the above are optionally substituted at asubstitutable position with groups that are independently C₁-C₄ alkyl,C₁-C₄ alkoxy, halogen, OH, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, amino, ormono or dialkylamino.

In still yet another aspect, the invention provides compounds of formulaV-ll, i.e., compounds of formula V-kk, wherein R₅ is C₁-C₆ alkoxyoptionally substituted with 1 group that is piperidinyl, pyrrolidinyl,morpholinyl, or piperazinyl wherein the cyclic portions of the above areoptionally substituted at a substitutable position with groups that areindependently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, OH, C₁-C₄ haloalkyl,C₁-C₄ haloalkoxy, amino, or mono or dialkylamino.

In still another aspect, the invention provides compounds of formulaV-mm, i.e., compounds of formula V-kk, wherein R₅ is C₁-C₆ alkoxyoptionally substituted with 1 group that is —SO₂—(C₁-C₄ alkyl),—SO₂—(C₁-C₄ haloalkyl), or —SO₂-phenyl wherein the cyclic portions ofthe above are optionally substituted at a substitutable position withgroups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, OH,C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, amino, or mono or dialkylamino.

In another aspect, the invention provides compounds of formula V-nn,i.e., compounds of formula V-kk, wherein R₅ is C₁-C₆ alkoxy optionallysubstituted with C₃-C₇ cycloalkyl (preferably C₃-C₆ cycloalkyl, morepreferably C₃-C₅ cycloalkyl, still more preferably, cyclopropyl) whereinthe cyclic portions of the above are optionally substituted at asubstitutable position with groups that are independently C₁-C₄ alkyl,C₁-C₄ alkoxy, halogen, OH, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, amino, ormono or dialkylamino.

In still another aspect, the invention provides compounds of formulaV-oo, i.e., compounds of formula V-jj, wherein R₅ is OH, amino, mono ordialkylamino, or C₁-C₆ haloalkoxy.

In yet another aspect, the invention provides compounds of formula V-pp,i.e., compounds of formula V-oo, wherein R₅ is amino, or mono ordi(C₁-C₆ alkyl)amino.

In yet still another aspect, the invention provides compounds of formulaV-qq, i.e., compounds of formula V-jj, wherein R₅ is C₁-C₆ haloalkoxyoptionally substituted with 1 OH.

In yet another aspect, the invention provides compounds of formula V-rr,i.e., compounds of formula V-qq, wherein R₅ is—CH₂C(halogen)₂C(halogen)₃, —CH₂CH₂C(halogen)₃, where each halogen isindependently F or Cl.

In still another aspect, the invention provides compounds of formulaV-ss, i.e., compounds of formula V-rr, wherein R₅ is —CH₂CF₂CF₃,—CH₂CH₂CF₃.

In another aspect, the invention provides compounds of formula V-tt,i.e., compounds of formula V-qq, wherein R₅ is—CH(CH₃)C(halogen)₂C(halogen)₃, —CH(CH₂halogen)₂, —CH(CH₃)C(halogen)₃,—CH(C(halogen)₃)₂, —C(CH₃)(C(halogen)₃)₂, or —CH(OH)C(halogen)₃, whereeach halogen is independently F or Cl.

In yet another aspect, the invention provides compounds of formula V-uu,i.e., compounds of formula V-tt, wherein R₅ is —CH(CH₃)CF₂CF₃,—CH(CH₂F)₂, —CH(CH₃)CF₃, —CH(CF₃)₂, —C(CH₃)(CF₃)₂, or —CH(OH)CF₃.

In still another aspect, the invention provides compounds of formulaV-vv, i.e., compounds of formula V-tt, wherein R₅ is—C(CH₃)(C(halogen)₃)₂ preferably each halogen is F.

In still yet another aspect, the invention provides compounds of formulaV-ww, i.e., compounds of formula V-tt, wherein R₅ is —CH(OH)C(halogen)₃.In one case, the stereogenic center in R₅ has the S-configuration. Inanother case, the stereogenic center in R₅ has the R-configuration.

In another aspect, the invention provides compounds of formula V-xx,i.e., compounds according to any one of formulas V-jj, V-kk, V-ll, V-mm,V-nn, V-oo, V-pp, V-qq, V-rr, V-ss, V-tt, V-uu, V-vv, or V-ww, whereinat least one of R₂₀ and R₄₀ is H; and R₈₀ is H, Cl, or OCF₃.

In still yet another aspect, the invention provides compounds of formulaV-yy, i.e., compounds of formula V-xx, wherein one of R₂₀ and R₄₀ ishalogen (in one aspect, F or Cl), OH, amino, mono ordi(C₁-C₄)alkylamino, hydroxy(C₁-C₄)alkyl, CF₃, or OCF₃.

In yet still another aspect, the invention provides compounds of formulaV-zz, i.e., compounds of formula V-xx, wherein both R₂₀ and R₄₀ are H.

In yet another aspect, the invention provides compounds of formulaV-zz1, i.e., compounds according to any one of formulas V-xx, V-yy, orV-zz wherein n is 1.

In yet still another aspect, the invention provides compounds of formulaV-zz2, i.e., compounds of formula V-zz1, wherein R₃ is halogen, OH,C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₂ haloalkyl, or C₁-C₂ haloalkoxy.

In still yet another aspect, the invention provides compounds of formulaV-zz3, i.e., compounds of formula V-zz2, wherein R₃ is halogen, OH,C₁-C₄ alkyl, C₁-C₄ alkoxy, CF₃, or OCF₃.

In still another aspect, the invention provides compounds of formulaV-zz4, i.e., compounds of formula V-zz3, wherein R₃ is halogen.

In yet another aspect, the invention provides compounds of formulaV-zz5, i.e., compounds of formula V-zz3, wherein R₃ is OH, C₁-C₄ alkyl,or C₁-C₄ alkoxy.

In yet still another aspect, the invention provides compounds of formulaV-zz6, i.e., compounds of formula V-zz3, wherein R₃ is CF₃ or OCF₃.

In still another aspect, the invention provides compounds of formulaV-zz7, i.e., compounds according to any one of formulas V-xx, V-yy, orV-zz wherein n is 0.

In another aspect, the invention provides compounds of formula V-zz8,i.e., compound according to formula V, wherein R₁ is H and R₃₀ is—(C₀-C₆ alkyl)-O—R₆.

In yet still another aspect, the invention provides compounds of formulaV-zz9, i.e., compounds of formula V-zz8, wherein R₆ is C₁-C₆ alkanoyl,wherein the alkyl portion of the alkanoyl group is substituted with oneor more halogens (preferably F or Cl, more preferably, F.) Or R₆ can be—(C₁-C₄ alkyl)-phenyl, —(C₁-C₄ alkanoyl)-phenyl, or phenyl, wherein thephenyl groups are optionally substituted with 1, 2, 3, 4, or 5 groupsthat are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, OH, C₁-C₄haloalkyl (such as CF₃), C₁-C₄ haloalkoxy (such as OCF₃), amino, or monoor di C₁-C₆ alkylamino.

In still yet another aspect, the invention provides compounds of formulaV-zz10, i.e., compound according to formula V-zz9, wherein R₃₀ is—(C₀-C₆ alkyl)-O—R₆.

In still yet another aspect, the invention provides compounds of formulaV-zz11, i.e., compound according to formula V-zz10, wherein R₃₀ is—(C₀-C₄ alkyl)-O—R₆.

In another aspect, the invention provides compounds of formula V-zz12,i.e., compounds according to any one of formulas V-zz8, V-zz9, V-zz10,or V-zz11, wherein at least one of R₂₀ and R₄₀ is H; and R₈₀ is H, Cl,or OCF₃.

In still yet another aspect, the invention provides compounds of formulaV-zz13, i.e., compounds of formula V-zz12, wherein one of R₂₀ and R₄₀ ishalogen (in one aspect, F or Cl), OH, amino, mono ordi(C₁-C₄)alkylamino, hydroxy(C₁-C₄)alkyl, CF₃, or OCF₃.

In yet still another aspect, the invention provides compounds of formulaV-zz14, i.e., compounds of formula V-zz12, wherein both R₂₀ and R₄₀ areH.

In yet another aspect, the invention provides compounds of formulaV-zz15, i.e., compounds according to any one of formulas V-zz8, V-zz9,V-z10, V-zz11, V-zz12, V-zz13, or V-zz14 wherein n is 1.

In yet still another aspect, the invention provides compounds of formulaV-zz16, i.e., compounds of formula V-zz15, wherein R₃ is halogen, OH,C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₂ haloalkyl, or C₁-C₂ haloalkoxy.

In still yet another aspect, the invention provides compounds of formulaV-zz17, i.e., compounds of formula V-zz16, wherein R₃ is halogen, OH,C₁-C₄ alkyl, C₁-C₄ alkoxy, CF₃, or OCF₃.

In still another aspect, the invention provides compounds of formulaV-zz18, i.e., compounds of formula V-zz17, wherein R₃ is halogen.

In yet another aspect, the invention provides compounds of formulaV-zz19, i.e., compounds of formula V-zz17, wherein R₃ is OH, C₁-C₄alkyl, or C₁-C₄ alkoxy.

In yet still another aspect, the invention provides compounds of formulaV-zz20, i.e., compounds of formula V-zz17, wherein R₃ is CF₃ or OCF₃.

In still another aspect, the invention provides compounds of formulaV-zz21, i.e., compounds according to any one of formulas V-zz8, V-zz9,V-zz10, V-zz11, V-zz12, V-zz13, or V-zz14 wherein n is 0.

In another aspect, the invention provides compounds of formula V-aaa,i.e., compounds of formula V, wherein R₁ is CH₂COOH and R₃₀ is —(C₀-C₆alkyl)-COR₅.

In yet another aspect, the invention provides compounds of formulaV-bbb, i.e., compounds of formula V-aaa, wherein R₅ is C₁-C₆ alkoxyoptionally substituted with 1 or 2 groups that are independently OH,C₁-C₄ alkoxy, piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl, C₃-C₇cycloalkyl, —SO₂—(C₁-C₄ alkyl), —SO₂—(C₁-C₄ haloalkyl), or —SO₂-phenylwherein the cyclic portions of the above are optionally substituted at asubstitutable position with groups that are independently C₁-C₄ alkyl,C₁-C₄ alkoxy, halogen, OH, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, amino, ormono or dialkylamino.

In still yet another aspect, the invention provides compounds of formulaV-ccc, i.e., compounds of formula V-bbb, wherein R₅ is C₁-C₆ alkoxyoptionally substituted with 1 group that is piperidinyl, pyrrolidinyl,morpholinyl, or piperazinyl wherein the cyclic portions of the above areoptionally substituted at a substitutable position with groups that areindependently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, OH, C₁-C₄ haloalkyl,C₁-C₄ haloalkoxy, amino, or mono or dialkylamino.

In still another aspect, the invention provides compounds of formulaV-ddd, i.e., compounds of formula V-bbb, wherein R₅ is C₁-C₆ alkoxyoptionally substituted with 1 group that is —SO₂—(C₁-C₄ alkyl),—SO₂—(C₁-C₄ haloalkyl), or —SO₂-phenyl wherein the cyclic portions ofthe above are optionally substituted at a substitutable position withgroups that are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, OH,C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, amino, or mono or dialkylamino.

In another aspect, the invention provides compounds of formula V-eee,i.e., compounds of formula V-bbb, wherein R₅ is C₁-C₆ alkoxy optionallysubstituted with C₃-C₇ cycloalkyl (preferably C₃-C₆ cycloalkyl, morepreferably C₃-C₅ cycloalkyl, still more preferably, cyclopropyl) whereinthe cyclic portions of the above are optionally substituted at asubstitutable position with groups that are independently C₁-C₄ alkyl,C₁-C₄ alkoxy, halogen, OH, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, amino, ormono or dialkylamino.

In still another aspect, die invention provides compounds of formulaV-fff i.e., compounds of formula V-aaa, wherein R₅ is OH, amino, mono ordialkylamino, or C₁-C₆ haloalkoxy.

In yet another aspect, the invention provides compounds of formulaV-ggg, i.e., compounds of formula V-fff, wherein R₅ is amino, or mono ordi(C₁-C₆ alkyl)amino.

In yet still another aspect, the invention provides compounds of formulaV-hhh, i.e., compounds of formula V-aaa, wherein R₅ is C₁-C₆ haloalkoxyoptionally substituted with 1 OH.

In yet another aspect, the invention provides compounds of formulaV-iii, i.e., compounds of formula V-hhh, wherein R₅ is—CH₂C(halogen)₂C(halogen)₃, —CH₂CH₂C(halogen)₃, where each halogen isindependently F or Cl.

In still another aspect, the invention provides compounds of formulaV-jjj, i.e., compounds of formula V-iii, wherein R₅ is —CH₂CF₂CF₃,—CH₂CH₂CF₃.

In another aspect, the invention provides compounds of formula V-kkk,i.e., compounds of formula V-hhh, wherein R₅ is—CH(CH₃)C(halogen)₂C(halogen)₃, —CH(CH₂halogen)₂, —CH(CH₃)C(halogen)₃,—CH(C(halogen)₃)₂, —C(CH₃)(C(halogen)₃)₂, or —CH(OH)C(halogen)₃, whereeach halogen is independently F or Cl.

In yet another aspect, the invention provides compounds of formulaV-lll, i.e., compounds of formula V-kkk, wherein R₅ is —CH(CH₃)CF₂CF₃,—CH(CH₂F)₂, —CH(CH₃)CF₃, —CH(CF₃)₂, —C(CH₃)(CF₃)₂, or —CH(OH)CF₃.

In still another aspect, the invention provides compounds of formulaV-mmm, i.e., compounds of formula V-kkk wherein R₅ is—C(CH₃)(C(halogen)₃)₂ preferably each halogen is F.

In still yet another aspect, the invention provides compounds of formulaV-nnn, i.e., compounds of formula V-kkk, wherein R₅ is—CH(OH)C((halogen)₃. In one case, the stereogenic center in R₅ has theS-configuration. In another case, the stereogenic center in R₅ has theR-configuration.

In another aspect, the invention provides compounds of formula V-ooo,i.e., compounds according to any one of formulas V-aaa, V-bbb, V-ccc,V-ddd, V-eee, V-fff, V-ggg, V-hhh, V-iii, V-jjj, V-kkk, V-lll, V-mmm, orV-nnn, wherein at least one of R₂₀ and R₄₀ is H; and R₈₀ is H, Cl, orOCF₃.

In still yet another aspect, the invention provides compounds of formulaV-ppp, i.e., compounds of formula V-ooo, wherein one of R₂₀ and R₄₀ ishalogen (in one aspect, F or Cl), OH, amino, mono ordi(C₁-C₄)alkylamino, hydroxy(C₁-C₄)alkyl, CF₃, or OCF₃.

In yet still another aspect, the invention provides compounds of formulaV-qqq, i.e., compounds of formula V-ooo, wherein both R₂₀ and R₄₀ are H.

In yet another aspect, the invention provides compounds of formulaV-rrr, i.e., compounds according to any one of formulas V-ooo, V-ppp, orV-qqq wherein n is 1 .

In yet still another aspect, the invention provides compounds of formulaV-sss, i.e., compounds of formula V-rrr, wherein R₃ is halogen, OH,C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₂ haloalkyl, or C₁-C₂ haloalkoxy.

In still yet another aspect, the invention provides compounds of formulaV-ttt, i.e., compounds of formula V-sss, wherein R₃ is halogen, OH,C₁-C₄ alkyl, C₁-C₄ alkoxy, CF₃, or OCF₃.

In still another aspect, the invention provides compounds of formulaV-uuu, i.e., compounds of formula V-ttt, wherein R₃ is halogen.

In yet another aspect, the invention provides compounds of formulaV-vvv, i.e., compounds of formula V-ttt, wherein R₃ is OH, C₁-C₄ alkyl,or C₁-C₄ alkoxy.

In yet still another aspect, the invention provides compounds of formulaV-www, i.e., compounds of formula V-ttt, wherein R₃ is CF₃ or OCF₃.

In still another aspect, the invention provides compounds of formulaV-xxx, i.e., compounds according to any one of formulas V-ooo, V-ppp, orV-qqq wherein n is 0.

In another aspect, the invention provides compounds of formula V-xxx1,i.e., compound according to formula V, wherein R₁ is CH₂CO₂H and R₃₀ is—(C₀-C₆ alkyl)-O—R₆.

In yet still another aspect, the invention provides compounds of formulaV-xxx2, i.e., compounds of formula V-xxx1, wherein R₆ is C₁-C₆ alkanoyl,wherein the alkyl portion of the alkanoyl group is substituted with oneor more halogens (preferably F or Cl, more preferably, F) Or R₆ can be—(C₁-C₄ alkyl)-phenyl, —(C₁-C₄ alkanoyl)-phenyl, or phenyl, wherein thephenyl groups are optionally substituted with 1, 2, 3, 4, or 5 groupsthat are independently C₁-C₄ alkyl, C₁-C₄ alkoxy, halogen, OH, C₁-C₄haloalkyl (such as CF₃), C₁-C₄ haloalkoxy (such as OCF₃), amino, or monoor di C₁-C₆ alkylamino.

In still yet another aspect, the invention provides compounds of formulaV-xxx3, i.e., compound according to formula V-xxx2, wherein R₃₀ is—(C₀-C₆ alkyl)-O—R₆.

In still yet another aspect, the invention provides compounds of formulaV-xxx4, i.e., compound according to formula V-xxx3, wherein R₃₀ is—(C₀-C₄ alkyl)-O—R₆.

In another aspect, the invention provides compounds of formula V-xxx5,i.e., compounds according to any one of formulas V-xxx1, V-xxx2, V-xxx3,or V-xxx4, wherein at least one of R₂₀ and R₄₀ is H; and R₈₀ is H, Cl,or OCF₃.

In still yet another aspect, the invention provides compounds of formulaV-xxx6, i.e., compounds of formula V-xxx5, wherein one of R₂₀ and R₄₀ ishalogen (in one aspect, F or Cl), OH, amino, mono ordi(C₁-C₄)alkylamino, hydroxy(C₁-C₄)alkyl, CF₃, or OCF₃.

In yet still another aspect, the invention provides compounds of formulaV-xxx7, i.e., compounds of formula V-xxx5, wherein both R₂₀ and R₄₀ areH.

In yet another aspect, the invention provides compounds of formulaV-xxx8, i.e., compounds according to any one of formulas V-xxx1, V-xxx2,V-xxx3, V-xxx4, V-xxx5, V-xxx6, or V-xxx7, wherein n is 1.

In yet still another aspect, the invention provides compounds of formulaV-xxx9, i.e., compounds of formula V-xxx8, wherein R₃ is halogen, OH,C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₂ haloalkyl, or C₁-C₂ haloalkoxy.

In still yet another aspect, the invention provides compounds of formulaV-xxx10, i.e., compounds of formula V-xxx9, wherein R₃ is halogen, OH,C₁-C₄ alkyl, C₁-C₄ alkoxy, CF₃, or OCF₃.

In still another aspect, the invention provides compounds of formulaV-xxx11, i.e., compounds of formula V-xxx10, wherein R₃ is halogen.

In yet another aspect, the invention provides compounds of formulaV-xxx12, i.e., compounds of formula V-xxx10, wherein R₃ is OH, C₁-C₄alkyl, or C₁-C₄ alkoxy.

In yet still another aspect, the invention provides compounds of formulaV-xxx13, i.e., compounds of formula V-xxx10, wherein R₃ is CF₃ or OCF₃.

In still another aspect, the invention provides compounds of formulaV-xxx10, i.e., compounds according to any one of formulas V-xxx1,V-xxx2, V-xxx3, V-xxx4, V-xxx5, V-xxx6, or V-xxx7 wherein n is 0.

In another aspect, the invention provides a compound according to any ofthe previously mentioned aspects of formulas I, II, III, IV, or V,wherein when R₂₀ is —(C₀-C₆ alkyl)-COR₅, it is preferably —(C₀-C₄alkyl)-COR₅, more preferably —(C₀-C₂ alkyl)-COR₅, and still morepreferably —COR₅, where R₅ is as previously defined.

In another aspect, the invention provides a compound according to any ofthe previously mentioned aspects of formulas I, II, III, IV, or V,wherein when R₃₀ is —(C₀-C₆ alkyl)-COR₅, it is preferably —(C₀-C₄alkyl)-COR₅, more preferably —(C₀-C₂ alkyl)-COR₅, and still morepreferably —COR₅, where R₅ is as previously defined.

In another aspect, the invention provides compounds of formula VI, i.e.,compounds of formula I, of the following structure.

and pharmaceutically acceptable salts thereof, wherein

-   R₅ is C₁-C₈ alkyl substituted with at least one halogen.

In still another aspect, the invention provides compounds of formulaVI-a, i.e., compounds of formula VI, wherein R₅ is C₂-C₈ alkylsubstituted with at least one halogen.

In still yet another aspect, the invention provides compounds of formulaVI-b, i.e., compounds of formula VI-a, wherein R₅ is C₃-C₇ alkylsubstituted with at least one halogen.

In yet still another aspect, the invention provides compounds of formulaVI-c, i.e., compounds of formula VI-b, wherein R₅ is C₃-C₆ substitutedwith at least one halogen.

In still another aspect, the invention provides compounds of formulaVI-d, i.e., compounds of formula VI-c, wherein R₅ is C₃-C₆ substitutedwith at least one fluoro group.

In yet another aspect, the invention provides compounds of formula VI-e,i.e., compounds of formula VI-d, wherein R₅ is R is C₃-C₆ substitutedwith at least two fluoro groups.

In still another aspect, the invention provides compounds of formulaVI-f, i.e., compounds of formula VI-e, wherein R₅ is a tert-butyl groupsubstituted with six fluoro groups.

In still another aspect, the invention provides compounds of formulaVI-g, i.e.,

compounds of formula VI-f, wherein R₅ is

In still another aspect, the invention provides a compound of formulaVI-h, i.e., a compound of formula VI, that is1,1,1,3,3,3-hexafluoro-2-methylpropan-2-yl4-((4-hydroxy-2-oxo-2H-chromen-3-yl)methyl)benzoate, or pharmaceuticallyacceptable salts thereof.

In still another aspect, the invention provides a compound of formulaVI-i, i.e., a compound of formula VI, that is1,1,1,3,3,3-hexafluoro-2-methylpropan-2-yl4-((4-hydroxy-2-oxo-2H-chromen-3-yl)methyl)benzoate.

In still another aspect, the invention provides a compound of formulaVI-j, i.e., a compound of formula VI-h, that is the sodium or potassiumsalt of 1,1,1,3,3,3-hexafluoro-2-methylpropan-2-yl4-((4-hydroxy-2-oxo-2H-chromen-3-yl)methyl)benzoate.

In still another aspect, the invention provides a compound of formulaVI-k, i.e., a compound of formula VI-j, that is the sodium salt.

Compounds where R₅ is H are the primary metabolites when compounds ofFormulas I, II, III, IV, V, and/or VI are administered to a mammal,including humans. They ate essentially devoid of activity at the VKERenzyme, but they are useful for monitoring drug levels in patients.

4-[(4-hydroxy-2-oxo-2H-chromen-3-yl)methyl]benzoic acid and the otheracids (i.e., compounds where R₅ is H) disclosed herein are very usefulfor preparing the desired halogenated esters of the invention.

Specific embodiments of the present invention include the followingcompounds:

The term “alkoxy” represents an alkyl group attached to the parentmolecular moiety through an oxygen bridge. Examples of alkoxy groupsinclude, for example, methoxy, ethoxy, propoxy, isopropoxy, pentoxy,tert-butyloxy and hexyloxy.

By “alkyl” is meant a straight or branched, non-cyclic, hydrocarbonExamples of alkyl groups include methyl, ethyl, propyl, isopropyl,n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl,hexyl, 2-hexyl, 3-hexyl, 3-methylpentyl, heptyl and octyl. “C₁-C₆ alkyl”denotes straight or branched, non-cyclic, alkyl groups having 1-6 carbonatoms. Likewise, “C₁-C₄ alkyl” denotes straight or branched, non-cyclic,alkyl groups having 1-4 carbon atoms.

The term “aryl” refers to an aromatic hydrocarbon ring system containingat least one aromatic ring. The aromatic ring may optionally be fused orotherwise attached to other aromatic hydrocarbon rings or non-aromatichydrocarbon rings.

Examples of aryl groups include, for example, phenyl, naphthyl,1,2,3,4-tetrahydronaphthalene and biphenyl. Preferred examples of arylgroups include phenyl, naphthyl, and anthracenyl. More preferred arylgroups are phenyl and naphthyl. Most preferred is phenyl.

The term “cycloalkyl” refers to a C₃-C₈ cyclic hydrocarbon. Examples ofcycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl and cyclooctyl.

The terms “halogen” or “halo” indicate fluorine, chlorine, bromine, andiodine.

The term “heterocycloalkyl” refers to a ring or ring system containingat least one heteroatom selected from nitrogen, oxygen, and sulfur,wherein said heteroatom is in a non-aromatic ring. The heterocycloalkylring is optionally fused to or otherwise attached to otherheterocycloalkyl rings and/or non-aromatic hydrocarbon rings and/orphenyl rings Preferred heterocycloalkyl groups have from 3 to 7 members.Examples of heterocycloalkyl groups include, for example,1,2,3,4-tetrahydroisoquinolinyl, piperazinyl, morpholinyl, piperidinyl,tetrahydrofuranyl, pyrrolidinyl, pyridinonyl, and pyrazolidinyl.Preferred heterocycloalkyl groups include piperidinyl, piperazinyl,morpholinyl, pyrrolidinyl, pyridinonyl, dihydropyrrolidinyl, andpyrrolidinone More preferred heterocycloalkyl groups includepiperidinyl, pyrrolidinyl, morpholinyl and piperazinyl.

The subject invention provides materials and methods for anticoagulanttreatment. Advantageously, the therapeutic compounds of the subjectinvention are stable in storage but have a shooter half-life in thephysiological environment than other drugs that are available foranticoagulant treatment; therefore, the compounds of the subjectinvention can be used with a lower incidence of side effects andtoxicity. In a preferred embodiment, the subject invention providestherapeutic anticoagulant compounds. The compounds of the subjectinvention can be used to treat at-risk populations thereby bringingrelief of symptoms, improving the quality of life, preventing acute andlong-term complications, reducing mortality and treating accompanyingdisorders.

Advantageously, the subject invention provides compounds that arereadily metabolized by the physiological metabolic drug detoxificationsystems. Specifically, in a preferred embodiment, the therapeuticcompounds of the subject invention contain a halogenated ester group,which does not detract from the ability of these compounds to provide atherapeutic benefit, but which makes these compounds more susceptible todegradation by hydrolases, particularly serum and/or cytosolicesterases. Advantageously, the compounds have been found to inhibit thevitamin K epoxide reductase (VKER) enzyme.

In addition to their activity at the VKER enzyme, the presence of atleast one halogen atom in the ester moiety gives these compounds certainadvantageous properties. Specifically, the addition of halogen to thesecompounds greatly reduces or eliminates their metabolism by CYP450,while at the same time greatly increasing esterase mediated hydrolysis.Thus, halogenation unexpectedly confers a predilection for esterasemetabolism when in the absence of such halogenation there is apredilection for CYP450 metabolism. This property gives the halogenatedester compounds important therapeutic advantages over non-halogenatedanalogs.

Because the halogenated compounds of the subject invention do not dependon CYP450 enzymes for metabolism, they are not likely to interact withother drugs at the CYP450 site and therefore they are safe to use inpatients who are already taking other medications, unlike theirnon-halogenated analogs. The subject invention further provides methodsof treatment comprising the administration of these compounds toindividuals in need of anticoagulant treatment.

In a further embodiment, the subject invention pertains to breakdownproducts that are formed when the therapeutic compounds of the subjectinvention are acted upon by esterases These breakdown products can beused, for example, as described herein to monitor the clearance of thetherapeutic compounds from a patient.

In yet a further embodiment, the subject invention provides methods forsynthesizing the compounds of the subject invention.

The subject invention provides materials and methods for the treatmentof coagulation disorders. Specifically, the subject invention providescompounds which are readily metabolized by the hydrolytic drugdetoxification systems preferentially to the oxidative drugdetoxification system. Specifically, this invention provides compoundsthat are susceptible to degradation by hydrolases, particularly serumand/or cytosolic esterases. This invention is also drawn to methods oftreating coagulation disorders.

This invention is drawn to compounds which are more easily metabolizedby the hydrolytic drug detoxification systems. This invention is alsodrawn to methods of treating coagulation disorders. Specifically, thisinvention provides analogs of drugs which have been designed to be moresusceptible to degradation by hydrolases, particularly serum and/orcytosolic esterases and methods of treatment comprising theadministration of these analogs to individuals.

Advantageously, use of the compounds of the subject invention can resultin a reduction of clinically relevant metabolic interactions involvingthe CYP system (particularly the CYP3A4 fraction) and helps to avoidADRs. These compounds do not rely on the CYP450 enzyme system, butinstead, exploit widely distributed esterases for metabolism andgeneration of a metabolite that is substantially pharmacologicallyinactive. This approach makes anticoagulant agents safer whilemaintaining efficacy, and also significantly reduces the financial riskof drug development.

In a preferred embodiment of the subject invention, therapeuticcompounds are provided which are useful in providing anticoagulanttreatment and which contain a halogenated ester group that is acted uponby hydrolytic enzymes, thereby breaking down the compound to asubstantially inactive and water soluble metabolite and facilitating itsefficient removal from the treated individual. As referred to herein, a“substantially inactive” metabolite may exhibit, e.g., less than orequal to about 10% (and more preferably less than or equal to about 5%;even more preferably less than or equal to about 2%; and most preferablyless than or equal to about 1%) of the parent compound's activity. In apreferred embodiment the therapeutic compounds are metabolized by plasmaesterases, tissue esterases, and/or non-oxidative/hydrolytic microsomalesterases.

A further aspect of the subject invention pertains to the breakdownproducts that are produced when the therapeutic compounds of the subjectinvention are acted upon by esterases. The presence of these breakdownproducts in the urine or serum can be used to monitor the rate ofclearance of the therapeutic compound from a patient.

The subject invention further provides methods of synthesizing theunique and advantageous therapeutic compounds of the subject invention.Particularly, methods of producing less toxic therapeutic agentscomprising introducing ester groups into therapeutic agents (targetdrugs) are taught. The ester linkage may be introduced into the compoundat a site that is convenient in the manufacturing process for the targetdrug. Additionally, the sensitivity of the ester linkage may bemanipulated by the addition of side groups which hinder or promote thehydrolytic activity of the hydrolases or esterases responsible forcleaving the drug at the ester locus. Methods of adding such sidegroups, as well as the side groups themselves, are well known to theskilled artisan and can be readily carried out utilizing the guidanceprovided herein.

The subject invention further provides anticoagulant treatmentcomprising the administration of a therapeutically effective amount ofhalogenated ester compounds to an individual in need of treatment.Accordingly, the subject invention provides halogenated esters andpharmaceutical compositions of these ester compounds. In a preferredembodiment the patient is a human; however, non-human animals also canbe treated.

Adverse drug-drug interactions (DDI), elevation of liver function test(LFT) values, and QT prolongation leading to torsades de pointes (TDP)are three major reasons why drug candidates fail to obtain FDA approval.All these causes are, to some extent, metabolism-based. A drug that hastwo metabolic pathways, one oxidative and one non-oxidative, built intoits structure is highly desirable in the pharmaceutical industry. Analternate, non-oxidative metabolic pathway provides the treated subjectwith an alternative drug detoxification pathway (an escape route) whenone of the oxidative metabolic pathways becomes saturated ornon-functional. While a dual metabolic pathway is desirable andnecessary in order to provide an escape metabolic route in case theprimary route is blocked, in the case of VKER inhibitors such as thedisclosed compounds of the subject invention, it is very important thatthe primary metabolism route be non-oxidative, because oxidativemetabolism is especially sensitive to drug-drug interactions. Thehalogenated esters of this invention ate primarily, if not only,metabolized by esterases, a non-oxidative enzymatic system, andtherefore are especially useful to treat patients who are taking othermedications.

Additional modifications of the compounds disclosed herein can readilybe made by those skilled in the art. Thus, analogs and salts of theexemplified compounds are within the scope of the subject invention.With a knowledge of the compounds of the subject invention, skilledchemists can use known procedures to synthesize these compounds fromavailable substrates. As used in this application, the term “analogs”refers to compounds which are substantially the same as another compoundbut which may have been modified by, for example, adding additional sidegroups. The term “analogs” as used in this application also may refer tocompounds which are substantially the same as another compound but whichhave atomic or molecular substitutions at certain locations in thecompound.

Analogs of the exemplified compounds can be readily prepared usingcommonly known, standard reactions. These standard reactions include,but are not limited to, hydrogenation, methylation, acylation,halogenation and acidification reactions. For example, new salts withinthe scope of the invention can be made by adding mineral bases, e.g.,NaOH, etc., or strong organic bases, e.g., triethanolamine, etc., inappropriate amounts to form the salt of the parent compound or itsderivative. Also, synthesis type reactions may be used pursuant to knownprocedures to add or modify various groups in the exemplified compoundsto produce other compounds within the scope of the invention.

Non-toxic pharmaceutically acceptable salts include, but are not limitedto salts of inorganic acids such as hydrochloric, sulfuric, phosphoric,diphosphonic, hydrobromic, and nitric or salts of organic acids such asformic, citric, malic, maleic, fumaric, tartaric, succinic, acetic,lactic, methanesulfonic, p-toluenesulfonic, 2-hydroxyethylsulfonic,salicylic and stearic. Similarly, pharmaceutically acceptable cationsinclude, but are not limited to sodium, potassium, calcium, aluminum,lithium and ammonium. Those skilled in the art will recognize a widevariety of non-toxic pharmaceutically acceptable addition salts. Thepresent invention also encompasses prodrugs of the compounds of FormulaI.

In a preferred embodiment, the subject invention provides compoundshaving Formula II:

Advantageously, the halogenated compounds are less favorable substratesfor cytochrome CYP450 than their non-halogenated analogs. They aretherefore more likely to be metabolized by esterases, which is desirablefor eliminating drug-drug interactions according to the subjectinvention.

The subject invention also provides processes for the manufacturing ofthe novel compounds The synthesis of these compounds can be achieved asshown in schemes 1 and 2.

In scheme 1, optionally substituted 4-hydroxycoumarin and an optionallysubstituted aromatic aldehyde are heated in a mixture of triethylamineand formic acid (2:5 molar ratio) to give the correspondinglysubstituted 3-benzyl-4-hydroxycoumarin wherein R₁ is hydrogen and n, R₃,R₂₀, R₃₀, and R₄₀ are defined as above.

Scheme 2 describes a synthetic pathway for preparing compounds where R₁is CH₂COOH. In scheme an optionally substituted 2,4-hydroxycoumarin, anoptionally substituted aromatic aldehyde, and Meldrum's acid are heatedin ethanol in the presence of ammonium acetate to give thecorrespondingly substituted chromen-3-yl-propionate, which in turn canbe hydrolyzed using a base, such as NaOH, followed by acidification inorder to provide the chromen-3-yl-propionic acid where n, R₃, R₂₀, R₃₀,and R₄₀ are defined as above.

Scheme 3 provides an alternative synthesis of C-3 substituted4-hydroxycoumarins. An optionally substituted 4-hydroxycoumarin and anaromatic aldehyde can be heated in a mixture of triethylamine and formicacid (2:5 molar ratio) to give an optionally substituted3-benzyl-4-hydroxycoumarin, which was in turn treated with 2.2 eq. of astrong base, such as BuLi, and quenched with carbon dioxide to give anoptionally substituted coumarin substituted phenyl-acetic acid.Corresponding esters can be obtained by treating the acid with variousalcohols in the presence of an acid, such as concentrated sulfuric acid.n, R₂, R₃, R₂₀, R₃₀, and R₄₀ are defined as above.

Scheme 4 illustrates an alternate method for preparing the compounds ofthe invention. An optionally substituted 4-hydroxycoumarin undergoesMichael addition with an optionally substituted methyl trans-cinnamatein an absolute alcohol, such as ethanol, in the presence of a base, suchas sodium ethoxide, at reflux temperature for approximately 16 hours.One of ordinary skill in the art will appreciate that other cinnamateesters can be used and that n, R₃, R₂₀, R₃₀, and R₄₀ are as defined asabove.

The subject invention further pertains to enantiomerically enrichedcompounds, and compositions comprising the compounds, for the treatmentof coagulation disorders. The isolated enantiomeric forms of thecompounds of the invention are substantially free from one another(i.e., in enantiomeric excess). In other words, the “R” forms of thecompounds are substantially free from the “S” forms of the compounds andare, thus, in enantiomeric excess of the “S” forms. Conversely, “S”forms of the compounds are substantially free of “R” forms of thecompounds and are, thus, in enantiomeric excess of the “R” forms. In oneembodiment of the invention, the isolated enantiomeric compounds are atleast about in 80% enantiomeric excess. In a preferred embodiment, thecompounds are in at least about 90% enantiomeric excess. In a morepreferred embodiment, the compounds are in at least about 95%enantiomeric excess. In an even more preferied embodiment, the compoundsare in at least about 97.5% enantiomeric excess. In a most preferredembodiment, the compounds are in at least 99% enantiomeric excess.

The subject invention also provides methods for treating coagulationdisorders comprising the administration of a therapeutically effectiveamount of the halogenated esters of this invention to an individual inneed of treatment. The therapeutic compounds of this invention haveapplicability in both veterinary and human clinical contexts. Further,the compounds of this invention have therapeutic properties similar tothose of the unmodified parent compound (COUMADIN). Accordingly, dosagerates and routes of administration of the disclosed compounds aresimilar to those already used in the art and known to the skilledartisan (see, for example, Physicians' Desk Reference, 54^(th) Ed.,Medical Economics Company, Montvale, N.J., 2000 or U.S. Pat. No.5,856,525 hereby incorporated by reference in its entirety).

The compounds of general Formula I may be administered orally,topically, parenterally, by inhalation or spray or rectally in dosageunit formulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles The term parenteral as usedherein includes percutaneous, subcutaneous, intravascular (e.g.,intravenous), intramuscular, or intrathecal injection or infusiontechniques and the like. In addition, there is provided a pharmaceuticalformulation comprising a compound of general Formula I and apharmaceutically acceptable carrier. One or more compounds of generalFormula I may be present in association with one or more non-toxicpharmaceutically acceptable carriers and/or diluents and/or adjuvants,and if desired other active ingredients. The pharmaceutical compositionscontaining compounds of general Formula I may be in a form suitable fororal use, for example, as tablets, troches, lozenges, aqueous or oilysuspensions, dispersible powders or granules, emulsion, hard or softcapsules, or syrups or elixirs.

Formulations are described in detail in a number of sources which arewell known and readily available to those skilled in the art. Forexample, Reminington's Pharmaceutical Science by E. W. Martin describesformulations which can be used in connection with the subject invention.In general, the compositions of the subject invention will be formulatedsuch that an effective amount of the bioactive compound(s) is combinedwith at least one suitable carrier, solvent, excipient, and/or adjuvantin order to facilitate effective administration of the composition.

In accordance with the invention, pharmaceutical compositionscomprising, as an active ingredient, an effective amount of one or moreof the compounds of the invention and one or more non-toxic,pharmaceutically acceptable carrier(s) and/or diluent(s). Examples ofsuch carriers for use in the invention include ethanol,dimethylsulfoxide, glycerol, silica, alumina, starch, and equivalentcarriers and diluents.

Further, acceptable carriers can be either solid or liquid. Solid formpreparations include powders, tablets, pills, capsules, cachets,suppositories and dispersible granules. A solid carrier can be one ormore substances which may act as diluents, flavoring agents,solubilizers, lubricants, suspending agents, binders, preservatives,tablet disintegrating agents or; an encapsulating material.

The disclosed pharmaceutical compositions may be subdivided into unitdoses containing appropriate quantities of the active component. Theunit dosage form can be a packaged preparation, such as packetedtablets, capsules, and powders in paper or plastic containers or invials or ampoules. Also, the unit dosage can be a liquid basedpreparation or formulated to be incorporated into solid food products,chewing gum, or lozenge.

The term “individual(s)” is defined as a single mammal to which isadministered a compound of the present invention. The mammal may be arodent, for example a mouse or a rat, or a non-rodent, for example apig, a horse, a rabbit, a goat, a cow, a cat, a dog, or can be a human.In a preferred embodiment, the individual is a human.

Following are examples which illustrate procedures for practicing theinvention. These examples should not be construed as limiting. Allpercentages are by weight and all solvent mixture proportions are byvolume unless otherwise noted. Reactions were performed in dry solventsunder an atmosphere of nitrogen unless otherwise specified, and werefollowed by thin-layer chromatography (TLC) on Analtech (0.25 mm)glass-packed precoated silica gel plates which were visualized by shortwave UV light or in an iodine chamber. The term “standard work-up”refers to addition of water to the reaction mixture, extraction withEtOAc (3×), washing the combined organic layers successively with waterand brine, drying over anhydrous Na₂SO₄, filtering and concentrating ona Buchi R-114 rotary evaporator. Chromatographic separations wereperformed on silica gel columns (Aldrich Silica Gel 70-230 mesh, 60 A)or on a Gilson liquid handler using a reverse phase Polaris C18 column(5 μ, 100×212). ¹H NMR spectra were recorded on a Nicolet/GE NT 300spectrometer.

EXAMPLE 1 Preparation of4-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid2,2,2-trifluoro-1-methyl-1-trifluoromethyl-ethyl ester

Triethylammonium formate (TEAF) is prepared by adding TEA (20.0 mL) toformic acid (16.5 mL) with ice cooling. To TEAF is added4-(2,2,2-trifluoro-1-methyl-1-trifluoromethyl-ethoxycarbonyl)benzaldelhyde(3.78 mL) and 4-hydroxychromen-2-one (6.0 g) and the resulting mixtureheated to 130-140° C. for 3 hours, cooled to room temperature, dilutedwith water, and extracted with EtOAc.

The organic layer is washed with brine, dined over MgSO4 and conc. invacuo to give a light yellow solid. The crude solid is recrystallizedfrom EtOH to give 4-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid2,2,2-trifluoro-1-methyl-1-trifluoromethyl-ethyl ester (1.95 g).

EXAMPLE 2 Preparation of4-Hydroxy-3-(3-oxo-1,3-dihydro-isobenzofuran-1-yl)-chromen-2-one

A solution of 4-hydroxy-chromen-2-one (650 mg) and2-carboxybenzyladehyde (300 mg) in EtOH is heated to reflux for 4 hours,cooled to room temperature then concentrated in vacuo to give a crudeoil, which is diluted with water.

The precipitated 4-hydroxy-chromen-2-one is collected by filtration (490mg).

A second crop of solid is collected from the mother liquor andtriturated with hot EtOAc and filtered to provide4-Hydroxy-3-(3-oxo-1,3-dihydro-isobenzofuran-1-yl)-chromen-2-one aswhite solid.

EXAMPLE 3 Preparation of2-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid chloromethylester

To a solution4-Hydroxy-3-(3-oxo-1,3-dihydro-isobenzofuran-1-yl)-chromen-2-one (60 mg)in ethanol is added 10% Pd/C (10 mg) then stirred under a hydrogenballoon for 12 hours The reaction mixture is filtered through a pad ofcelite and the filtrate concentrated in vacuo to give2-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid as white solid(50 mg). MS: 295[M-H].

A solution of 2-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid ina 5% sodium bicarbonate solution is added to a solution of 1.5equivalent of chloromethylchlorosulfate in methylene chloride.Tetrabutylammonium hydrogensulfate (catalytic amount) is added, and themixture stirred vigorously for 5 hours. The organic layer is dried overMgSO4 and conc. in vacuo to give2-(4-Hydroxy-2-oxo-2H-chromen-3-ylmethyl)-benzoic acid chloromethylester as white solid.

EXAMPLE 4 Preparation of 1,1,1,3,3,3-hexafluoro-2-methylpropan-2-yl4-((4-hydroxy-2-oxo-2H-chromen-3-yl)methyl)benzoate

Step 1 The preparation of 1,1,1,3,3,3-hexafluoro-2-methylpropan-2-yl4-formylbenzoate

A mixture of 41.1 g (274 mmol) 4-carboxybenzaldehyde, 50 g (274 mmol)1,1,1,3,3,3-hexafluoro-2-methyl-2-propanol, and 33.4 g (274 mmol) DMAPin 700 mL DCM was stirred until homogeneous (approximately 0.5 in). Thesolution was cooled over an ice bath, under Ar, and 52.3 g (274 mmol)EDCI was added portion-wise. The reaction was stirred at RT for 48 hr.and concentrated to an oil on the rotovap. The oil was taken up with EAand washed with water, 2× with dip. Citric acid, 2× with dip Sodiumbicarbonate, and brine. The organic layer was dried over sodium sulfateand concentrated to 25.5 g pale yellow solid.

Step 2: Preparation of the Title Compound

A mixture of 22 g (70 mmol) of the benzaldehyde, 11.3 g (70 mmol) of4-hydroxycoumarin, and 70 mL of 1.2:1 (v/v) TEA/formic acid was heatedto 140 C under nitrogen for 2 hrs. (3 hrs would have been better)Reaction progress was monitored by TLC using 1:1 (1% HCOAc/EA)/HexaneMixture was allowed to cool briefly and treated with 50 mL THF (toinhibit crystallization) and poured into 500 mL of EA. The EA layer waswashed 3× with water, once with brine and then dried over sodiumsulfate. Filtration and concentration provided a white solid which canbe recrystallized from EA or acetone.

If desired, the title compound can be converted into a pharmaceuticallyacceptable salt, such as die sodium salt.

EXAMPLE 5 Preparation of 3,3,4,4,4-pentafluorobutan-2-yl4-((4-hydroxy-2-oxo-2H-chromen-3-yl)methyl)benzoate

Step 1: Preparation of 3,3,4,4,4-pentafluorobutan-2-yl 4-formylbenzoate(3)

A mixture of 4-carboxybenzaldehyde (21.9 g, 145.9 mmol),3,3,4,4,4-pentafluoro-2-butanol (24.1 g, 146.9 mmol), EDC (33.5 g, 174.8mmol) and DMAP (18.1 g, 148.1 mmol) was dissolved in DMF (60 ml) at rt.It was stirred for 36 h at rt. Hexane was added, it was washed with 1 NHCl, sat NaHCO₃ and brine. The aqueous layers were extracted three timeswith hexane. It was dried over Na₂SO₄, filtered, concentrated, and theresidue was purified by silica gel chromatography (ethyl acetate:hexane1:10) to yield the desired aldehyde as a yellow oil (67%).

Step 2: Preparation of the Title Compound

Formic acid (35.8 ml) was added to 4-Hydroxycoumarin (15.8 g, 97.5 mmol)and aldehyde 3 (28.9 g, 97.6 mmol). Triethylamine (43 ml) was added(exothermic) at 0° C. It was warmed to 140° C. and stirred for 4 h atthis temperature. The yellow solution was cooled to rt, ethyl acetatewas added, it was washed with 1 N HCl and brine, it was dried overNa₂SO₄ and the solvent was removed. The slightly yellow solid wasrecristallized from ethylacetate to yield the title compound as a whitesolid in 98% purity (60% yield).

The sodium salt was made as follows: the free acid (21.39 g, 48.35 mmol)and NaHCO₃ (4.06 g, 48.30 mmol) were dissolved in acetonitrile (400 ml)and water (100 ml) and lyophilized to yield the Na-salt, as a whitesolid.

EXAMPLE 6 Preparation of (S)-((R)-3,3,4,4,4-pentafluorobutan-2-yl)2-(6-methoxynaphthalen-2-yl)propanoate

Step 1: Preparation of (2S)-3,3,4,4,4-pentafluorobutan-2-yl2-(6-methoxynaphthalen-2-yl)propanoate (mix of diastereomers) (6)

A mixture of (S)-naproxen (9.23 g, 40.1 mmol), racemic3,3,4,4,4-pentafluoro-2-butanol (6.58 g, 40.1 mmol), EDC (9 20 g, 48.0mmol) and DMAP (4.89 g, 40.0 mmol) was dissolved in CH₂Cl₂ (40 mL) atroom temperature. After stirring for 8 h at room temperature, themixture was diluted with CH₂Cl₂, then washed successively with 1 N HCl,sat. NaHCO₃, and brine. After drying over Na₂SO₄ and concentrating, amixture of diastereomeric naproxen esters was obtained as a white solid.

Step 2: Small Amounts of the Diastereomers Were Separated via ReversePhase HPLC (C₁₈-column, with 50% to 70% CH₃CN/Water)

(S,S)-Naproxen ester (single diastereomer) ¹H NMR (CDCl₃, 400 MHz) δ7.70 (d, J=8.8 Hz, 2H), 7.65 (d, J=1.2 Hz, 1H), 7.37 (dd J=1.8, 8.6 Hz,1H), 7.15 (dd, J=2.8, 8.8 Hz, 1H), 7.12 (d, J=2.4 Hz, 1H), 5.35-5.42 (m,1H), 3.92 (s, 3H), 3.90 (q, J=7.2 Hz, 1H), 1.60 (d, J=7.2 Hz, 3H), 1.39(d, J=6.0 Hz, 3H); ¹⁹F NMR (CDCl₃, 376 MHz) δ −82.0 (s, 3F), −122.7 (dd,J=7.0, 278.2 Hz, 1F), −128.6 (dd, J=16.0, 278.9 Hz, 1F).

(S,R)-Naproxen ester (single diastereomer) ¹H NMR (CDCl₃, 400 MHz) δ7.71 (d, J=8.4 Hz, 2H), 7.66 (d, J=1.2 Hz, 1H), 7.38 (dd, J=1.8, 8.6 Hz,1H), 7.15 (dd, J=2,4, 8.8 Hz, 1H), 7.12 (d, J=2.4 Hz, 1H), 5.39-5.47 (m,1H), 3.92 (s, 3H), 3.90 (q, J=7.2 Hz, 1H), 1.59 (d, J=7.2 Hz, 3H), 1.27(d, J=64 Hz, 3H); ¹⁹F NMR (CDCl₃, 376 MHz) δ −82.0 (s, 3F), −122.7 (dd,J=7.0, 278.2 Hz, 1F), −128.6 (dd, J=16.0, 279.1 Hz, 1F).

Step 3: The Naproxen Resolving Agent was Hydrolytically Removed.

The (S,S)-Naproxen ester (3.83 g, 10.18 mmol) from step 2 was treatedwith 1 N KOH (19 ml) and THF (19.5 mL) at room temperature. The emulsionwas stirred at room temperature and became a clear solution after 3 h.After stirring for one additional hour, CH₂Cl₂ (50 mL) was added and thesolution was washed with sat. NaHCO₃ (four times) and dried over Na₂SO₄and filtered to afford a solution of the S isomer of the alcohol. Thesolution was used directly in the next step, without purification.

Step 4: The Ester is Formed

To a solution of the S isomer of the alcohol from step 3) was added4-carboxybenzaldehyde (3.35 g, 22.3 mmol), EDC (5.14 g, 26.8 mmol) andDMAP (2.70 g, 22.1 mmol). The reaction mixture was stirred for 16 h atroom temperature. Ethyl acetate was added and the organic layer waswashed successively with sat. NaHCO₃(aq) and brine. After drying overNa₂S(O₄, filtering, and concentrating, the residue was purified bysilica gel chromatography (ethyl acetate:hexane 1:10) to yield(S)-4-formyl-benzoic acid 2,2,3,3,3-pentafluoro-1-methyl-propyl ester asa yellow oil (82%).

Step 5: The Final Coupling Preparation of(S)-3,3,4,4,4-pentafluorobutan-2-yl4-((4-hydroxy-2-oxo-2H-chromen-3-yl)methyl)benzoate

4-Hydroxycoumarin (1.367 g, 8.44 mmol) and (S)-4-formyl-benzoic acid2,2,3,3,3-pentafluoro-1-methyl-propyl ester (2.505 g, 8.46 mmol) weredissolved in formic acid (3.0 mL) and Et₃N (3.6 mL) at 0° C. Afterstirring at 140° C. for 4 h, the yellow solution was cooled to rt, EtOAcwas added, and the organic layer was washed successively with 1 N HCland brine. After drying over Na₂SO₄ and concentrating, the pale yellowsolid was purified twice by silica gel chromatography (DCM:MeOH 100:6and DCM:MeOH 100:5) to yield the title compound in 92.5% ee asdetermined by chiral HPLC.

The sodium salt was made as follows: The free acid (1.60 g, 3.62 mmol)and NaHCO₃ (303 mg, 3.62 mmol) were dissolved in acetonitrile (25 mL)and water (5 mL), and then lyophilized to yield the desired Na-salt, asa white solid. MS m/e 465 (MNa⁺), 441 (M-H); ¹H NMR (DMSO-d₆) δ7.76-7.80 (m, 3H), 7.43 (d, J=8.3 Hz, 2H), 7.31 (dt, 1H), 7.02-7.08 (m,2H), 5.71-5.79 (m, 1H), 3.70 (s, 2H), 1.48 (d, J=6.9 Hz, 3H); ¹⁹F NMR(DMSO-d₆) δ −81.3 (s, 3F), −121.2 (dd, J=7.0, 276.7 Hz, 1F), −128 2 (d,J=17.1, 276.7 Hz, 1F).

EXAMPLE 7 Preparation of (R)-3,3,4,4,4-pentafluorobutan-2yl4-((4-hydroxy-2-oxo-2H-chromen-3-yl)methyl)benzoate

Using methods and procedures essentially analogous to those in Example6, the (S,R) diastereomer from Example 6, step 2 was hydrolyzed toafford the desired (R)-isomer of the alcohol, which was then coupledwith 4-carboxybenzaldehyde to afford (R)-3,3,4,4,4-pentafluorobutan-2-yl4-formylbenzoate, which was then coupled with 4-hydroxycoumarin toafford the title compound.

The sodium salt was made as follows: the free acid (1.605 g, 3.63 mmol)and NaHCO₃ (303 mg, 3.62 mmol) were dissolved in acetonitrile (20 mL),water (5 mL), and then lyophilized to yield the Na-salt, as a whitesolid, MS m/e 465 (MNa⁺), 441 (M-H); ¹H NMR (DMSO-d₆) δ 7.81 (dd, J=1.1,7.9 Hz, 1H), 7.77-7.80 (m, 2H), 7.43 (d, J=8.3 Hz, 2H), 7.32-7.36 (m,1H), 7.05-7.11 (m, 2H), 5.71-5.80 (m, 1H), 3.72 (s, 2H), 1.49 (d, J=6.1Hz, 3H); ¹⁹F NMR (DMSO-d₆) δ −81.3 (s, 3F), −121.2 (dd, J=6.0, 265.6 Hz,1F), −1.282 (dd, J=16.2, 265.8 Hz, 1F).

EXAMPLE 8

The following compounds were prepared essentially according to themethods and schemes described herein.

Name 3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-3-phenylpropanoic acid methyl3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-3- phenylpropanoate ethyl3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-3-phenylpropanoate3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-3-phenylpropanamide 2-hydroxyethyl3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-3- phenylpropanoate2,2,3,3,3-pentafluoropropyl 3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-3-phenylpropanoate 3,3,3-trifluoropropyl3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-3- phenylpropanoate2-(phenylsulfonyl)ethyl 3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-3-phenylpropanoate 2-(methylsulfonyl)ethyl3-(4-hydroxy-2-oxo-2H-chromen-3-yl)- 3-phenylpropanoate2-(4-fluorophenyl)ethyl 3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-3-phenylpropanoate 2,2,2-trifluoro-1,1-dimethylethyl3-(4-hydroxy-2-oxo-2H- chromen-3-yl)-3-phenylpropanoate2,2,2-trifluoro-1-phenylethyl 3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-3-phenylpropanoate2-[(4-hydroxy-2-oxo-2H-chromen-3-yl)methyl]benzoic acid{4-[(4-hydroxy-2-oxo-2H-chromen-3-yl)methyl]phenyl}acetic acid{4-[(4-hydroxy-2-oxo-2H-chromen-3-yl)methyl]phenyl}acetic acid methyl2-[(4-hydroxy-2-oxo-2H-chromen-3-yl)methyl]benzoate3-{2-[(4-hydroxy-2-oxo-2H-chromen-3- yl)methyl]phenyl}propanoic acidethyl 3-{2-[(4-hydroxy-2-oxo-2H-chromen-3- yl)methyl]phenyl}propanoate3-[4-hydroxy-2-oxo-2H-chromen-3-yl)-3-(4- methoxyphenyl)propanoic acidsodium 3-[3-ethoxy-1-(4-methoxyphenyl)-3-oxopropyl]-2-oxo-2H-chromen-4-olate 3-(4-hydroxy-2-oxo-2H-chromen-3-yl)butanoic acidethyl 3-[4-hydroxy-2-oxo-2H-chromen-3-yl)butanoate4-[3-ethoxy-1-(4-hydroxy-2-oxo-2H-chromen-3-yl)-3- oxopropyl]benzoicacid ethyl 4-[3-ethoxy-1-(4-hydroxy-2-oxo-2H-chromen-3-yl)-3-oxopropyl]benzoate 3-(4-hydroxy-2-oxo-2H-chromen-3-yl)hexanoic acidethyl 3-(4-hydroxy-2-oxo-2H-chromen-3-yl)hexanoate3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-5-methylhexanoic acid ethyl3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-5-methylhexanoate3-(4-chlorophenyl)-3-(4-hydroxy-2-oxo-2H-chromen-3- yl)propanoic acid3-(3,4-dichlorophenyl)-3-(4-hydroxy-2-oxo-2H-chromen-3- yl)propanoicacid 3-(2,3-dihydro-1,4-benzodioxin-6-yl)-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)propanoic acid ethyl3-(2,3-dihydro-1,4-benzodioxin-6-yl)-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)propanoate4-[bis(4-hydroxy-2-oxo-2H-chromen-3-yl)methyl]benzoic acid3-(4-hydroxy-2-oxo-2H-chromen-3-yl)propanoic acid ethyl3-(4-hydroxy-2-oxo-2H-chromen-3-yl)propanoate cyclohexyl3-(4-hydroxy-2-oxo-2H-chromen-3-yl)propanoate methyl4-[bis(4-hydroxy-2-oxo-2H-chromen-3- yl)methyl]benzoate5-[(4-hydroxy-2-oxo-2H-chromen-3-yl)methyl]-2- methoxybenzoic acidmethyl 5-[(4-hydroxy-2-oxo-2H-chromen-3-yl)methyl]-2- methoxybenzoate5-[(4-hydroxy-2-oxo-2H-chromen-3-yl)methyl]-2- isopropoxybenzoic acidmethyl 5-[(4-hydroxy-2-oxo-2H-chromen-3-yl)methyl]-2- isopropoxybenzoateisopropyl 5-[(4-hydroxy-2-oxo-2H-chromen-3-yl)methyl]-2-isopropoxybenzoate ethyl 2-{4-[(4-hydroxy-2-oxo-2H-chromen-3-yl)methyl]phenoxy}-2-methylpropanoate methylN-{4-[(4-hydroxy-2-oxo-2H-chromen-3- yl)methyl]benzoyl}-L-valinatemethyl N-{4-[(4-hydroxy-2-oxo-2H-chromen-3- yl)methyl]benzoyl}glycinatemethyl N-[4-{(4-hydroxy-2-oxo-2H-chromen-3-yl)methyl]benzoyl}-N-methylglycinate3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-3-[4-(trifluoromethoxy)phenyl]propanoic acid

methyl N-[3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-3-(4-methoxyphenyl)propanoyl]glycinate{4-[(4-hydroxy-2-oxo-2H-chromen-3-yl)methyl]phenoxy}acetic acid methyl{4-[(4-hydroxy-2-oxo-2H-chromen-3- yl)methyl]phenoxy}acetate ethyl2-[bis(4-hydroxy-2-oxo-2H-chromen-3-yl)methyl]benzoate

3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-3-(1-naphthyl)propanoic acid methyl3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-3-(1- naphthyl)propanoate3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-3-(2-naphthyl)propanoic acid methyl3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-3-(2- naphthyl)propanoate3-{4-[(4-hydroxy-2-oxo-2H-chromen-3- yl)methyl]phenyl}propanoic acidmethyl 3-{4-[(4-hydroxy-2-oxo-2H-chromen-3- yl)methylphenyl}propanoate4-hydroxy-3-(4-hydroxybenzyl)-2H-chromen-2-one4-[(4-hydroxy-2-oxo-2H-chromen-3-yl)methyl]phenyl propionate4-[(4-hydroxy-2-oxo-2H-chromen-3-yl)methyl]phenyl pivalate4-[(4-hydroxy-2-oxo-2H-chromen-3-yl)methyl]phenyl benzoate4-[(4-hydroxy-2-oxo-2H-chromen-3-yl)methyl]phenyl 2,6- dimethylbenzoate4-[(4-hydroxy-2-oxo-2H-chromen-3-yl)methyl]phenyl 2- methylbenzoate6-[(4-hydroxy-2-oxo-2H-chromen-3-yl)methyl]-2-naphthoic acid ethyl6-[(4-hydroxy-2-oxo-2H-chromen-3-yl)methyl]-2- naphthoate3-(benzylamino)-4-hydroxy-2H-chromen-2-one3-(4-hydroxy-2-oxo-2H-chromen-3-yl)-3-[4-(trifluoromethoxy)phenyl]propanoic acid4-hydroxy-3-(3-oxo-1,3-dihydro-2-benzofuran-1-yl)-2H- chromen-2-one3-benzyl-4-hydroxy-2H-chromen-2-one4-hydroxy-3-(3-hydroxy-1-phenylpropyl)-2H-chromen-2-one3-(4-hydxoxy-2-oxo-2H-chromen-3-yl)-3-[4-(trifluoromethoxy)phenyl]propanoic acid(3S)-3-(3,4-dichlorophenyl)-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)propanoic acid(3R)-3-(3,4-dichlorophenyl)-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)propanoic acid 2-benzyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)propanoicacid ethyl 2-benzyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)propanoate3-cyclohexyl-3-(4-hydroxy-2-oxo-2H-chromen-3-yl)propanoic acid ethyl3-cyclohexyl-3-(4-hydroxy-2-oxo-2H-chromen-3- yl)propanoate ethyl2-(4-hydroxy-2-oxo-2H-chromen-3-yl)butanoate(4-hydroxy-2-oxo-2H-chromen-3-yl)(phenyl)acetic acid ethyl(4-hydroxy-2-oxo-2H-chromen-3-yl)(phenyl)acetate4-[(4-hydroxy-2-oxo-2H-chromen-3-yl)methyl]benzoic acid methyl4-[(4-hydroxy-2-oxo-2H-chromen-3-yl)methyl]benzoate ethyl4-[(4-hydroxy-2-oxo-2H-chromen-3-yl)methyl]benzoate butyl4-[(4-hydroxy-2-oxo-2H-chromen-3-yl)methyl]benzoate sodium3-{4-[(2-hydroxyethoxy)carbonyl]benzyl}-2-oxo-2H- chromen-4-olateisopropyl 4-[(4-hydroxy-2-oxo-2H-chromen-3- yl)methyl]benzoate2,2-dimethylpropyl 4-[(4-hydroxy-2-oxo-2H-chromen-3- yl)methyl]benzoate2-methoxyethyl 4-[(4-hydroxy-2-oxo-2H-chromen-3- yl)methyl]benzoate2-pyrrolidin-1-ylethyl 4-[(4-hydxoxy-2-oxo-2H-chromen-3-yl)methyl]benzoate 2,2,3,3,3-pentafluoropropyl4[(4-hydroxy-2-oxo-2H-chromen-3- yl)methyl]benzoate2-(methylsulfonyl)ethyl 4-[(4-hydroxy-2-oxo-2H-chromen-3-yl)methyl]benzoate 3,3,3-trifluoropropyl4-[(4-hydroxy-2-oxo-2H-chromen-3- yl)methyl]benzoate2,2,3,3,3-pentafluoro-1-methylpropyl 4-[(4-hydroxy-2-oxo-2H-chromen-3-yl)methyl]benzoate 4-fluorobenzyl4-[(4-hydroxy-2-oxo-2H-chromen-3- yl)methyl]benzoate2-(4-fluorophenoxy)ethyl 4-[(4-hydroxy-2-oxo-2H-chromen-3-yl)methyl]benzoate 2-(phenylsulfonyl)ethyl4-[(4-hydroxy-2-oxo-2H-chromen-3- yl)methyl]benzoate cyclopropylmethyl4-[(4-hydroxy-2-oxo-2H-chromen-3- yl)methyl]benzoate2-fluoro-1-(fluoromethyl)ethyl 4-[(4-hydroxy-2-oxo-2H-chromen-3-yl)methyl]benzoate 2,2,2-trifluoro-1-methylethyl4-[(4-hydroxy-2-oxo-2H-chromen- 3-yl)methylbenzoate2,2,2-trifluoro-1-(trifluoromethyl)ethyl 4-[(4-hydroxy-2-oxo-2H-chromen-3-yl)methyl]benzoate phenyl4-[(4-hydroxy-2-oxo-2H-chromen-3-yl)methyl]benzoate 2,3-dimethylphenyl4-[(4-hydroxy-2-oxo-2H-chromen-3- yl)methyl]benzoate 2-methylphenyl4-[(4-hydroxy-2-oxo-2H-chromen-3- yl)methyl]benzoate2,2,2-trifluoro-1-methyl-1-(trifluoromethyl)ethyl 4-[(4-hydroxy-2-oxo-2H-chromen-3-yl)methyl]benzoate 2,6-dimethylphenyl4-[(4-hydroxy-2-oxo-2H-chromen-3- yl)methyl]benzoate2-(phenylsulfinyl)ethyl 4-[(4-hydroxy-2-oxo-2H-chromen-3-yl)methyl]benzoate 4-fluoro-2-methylphenyl4-[(4-hydroxy-2-oxo-2H-chromen-3- yl)methyl]benzoate2,2,3,3,3-pentafluoro-1-methylpropyl 4-[(4-hydroxy-2-oxo-2H-chromen-3-yl)methyl]benzoate 2,2,3,3,3-pentafluoro-1-methylpropyl4-[(4-hydroxy-2-oxo-2H- chromen-3-yl)methyl]benzoate(1S)-2,2,2-trifluoro-1-hydroxyethyl 4-[(4-hydroxy-2-oxo-2H-chromen-3-yl)methylbenzoate (1R)-2,2,2-trifluoro-1-hydroxyethyl4-[(4-hydroxy-2-oxo-2H- chromen-3-yl)methyl]benzoate4-hydroxy-3-(3-oxo-phenylbutyl)-2H-chromen-2-one

EXAMPLE 9 Effects of Compounds on Vitamin K Epoxide Reductase Activity

Compounds of the subject invention were tested against vitamin K epoxidereductase.

Briefly: increasing concentrations of compounds were incubated in thepresence of vitamin K epoxide and in the presence of a bovine microsomalpreparation containing vitamin K epoxide reductase. The amount ofresidual vitamin K epoxide at the end of the incubation period wasdirectly proportional to the inhibitory activity of the test compoundson the enzyme.

The tests were performed as follows:

Microsomes were prepared from fresh cow liver according to the methoddescribed in: “Purification of gamma-glutamyl carboxylase from bovineliver. Wu S M, Mutucumarana V P, and Stafford D W. Methods in Enzymology(1997) 282:346-57”.

Serial dilutions of test compounds were prepared as follows: Dissolvethe test compounds to a final dilution of 10 mM either in water or inDMSO (if not soluble in water). From this mother solution, prepare 2further dilutions by diluting it with water: one 200 μM solution and one5 mM solution. Prepare a series of tubes as follows:

TABLE 1 Tube# Substrate Water (μL) 1 30 μL of 200 μM solution  0 2 20 μLof 200 μM solution 10 3 10 μL of 200 μM solution 20 4 45 μL of 5 μMsolution — 5 30 6 30 7 30 8 30 9 30

Remove 15 μL from tube 4 and add to tube 5, vortex, then remove 15 μLfrom tube 5 and add to tube 6, vortex, etc. until 15 μL, is added totube 9, Vortex and then remove 15 μL from tube 9.

Prepare another set of 4 tubes and add 30 μL of water.

A reaction mixture consisting of 600 μL buffer (2.5M NaCl, 0.125M MOPS,pH7.5), 520 μL water; and 150 μL of 10% CHAPS was prepared The tubeswere kept on ice for 5 minutes and then 500 μL of microsomal preparationwas added. The mixture was mixed by vortex and kept on ice for 10 minfor sufficient solubilization To this was added 150 μL of vitamin Kepoxide solution (1.5 mg/ml in isopropanol), then again vortexed andkept on ice for 5 minutes An aliquot (70 μL) of this reaction mix wasadded to each one of the series of tubes prepared as above andcontaining serial dilutions of test compounds in 30 μL of water. Thetubes were then vortexed and then kept on ice for 5 min. To 2 of thewater-containing tubes was added 500 μL of a stop reagent consisting of5 volumes of 50 mM AgNO₃ and 5 volumes of isopropanol. These 2 tubeswere used to measure a zero value.

The tubes were placed in a 30C mixer for 3 min and 5 μL of 100 mM DTTsolution in water was added. The tubes were then vortexed and kept inthe dark without shaking for another 20 min, at the end of which 500 μL,of the stop reagent was added.

To each tube was then added 600 μL of a 100 μg/ml solution of vitamin Ein hexane, the tubes were capped and then vortexed for 1 minute. Thetubes were then centrifuged for 5 min at 5,000 g, and the upper layer(the hexane layer) was transferred to a series of fresh tubes. Thehexane was evaporated at room temperature in the dark using a speedvac,and the resulting pellet was resuspended in 100 μL of methanol.

The amount of vitamin K epoxide in each sample was then measured using aHPLC determination method. Residual vitamin K epoxide was then plottedagainst test compound concentration. The results are shown in FIGS. 1-9.

EXAMPLE 10 Metabolism in Pooled Human Microsomes

Pooled human liver microsomes were used as an in vitro model of drugmetabolism. These microsomes contain both esterase and CYP450 drugmetabolizing enzymes. Pooled human microsomes were suspended in Trisbuffer (50 mM, pH 7.4) at a final concentration of 1 mg/mL of microsomalprotein. Test compounds dissolved in acetonitrile:DMSO (1:99) were addedto a final concentration of 2 μM Incubations were performed at 37° C.and samples (50 μL) were collected after 5, 15, 30, 60 and 90 minutesand then were precipitated by the addition of 100 μL of acetonitrilecontaining Internal Standard and centrifuged at 14,000 rpm for 15 min at4° C. Samples were analyzed by LC/MS/MS for the content of parent drug.

To determine the role of CYP450 in the metabolism, incubations were runeither with or without an NADPH regenerating system—NADPH is an obligatecofactor for CYP450 enzymes. Incubations that included NADPH cofactorrepresent the total metabolism by CYP450+ esterase. Incubations that donot contain any NADPH represent esterase metabolism alone. Thus, whenthe relative decline of parent drug observed is greater in the presenceof NADPH, the metabolism is CYP450-mediated. When the relative declineis equivalent in the presence and absence of cofactor the metabolism isesterase mediated.

An additional set of incubations was run as a control: these incubationsdid not contain microsomes and established the stability of the compoundin the test system. All of the compounds were stable.

The test compounds had the general formula;

wherein R represents a group capable of forming an ester moiety. Similarstructures were tested such that the only difference was the presence orthe absence of a halogen atom in the ester group. Results are shown inFIGS. 12-14.

Similarly, compounds were tested in which R is CH₃, CH₂—CH₃, (CH₂)₃CH₃,CH₂—CH₂—OH, CH₂—C(CH₃)₃, CH₂—CH₂—O—CH₃, 1-pyrrolidinylethyl,CH₂—CH₂—SO₂—CH₃, benzyl, CH₂—CH₂—O-Phenyl, CH₂—CH₂—SO₂-Phenyl,CH₂-Cyclopropyl, phenyl, substituted phenyl. In all cases CYP450 waseither the only metabolic agent, or if esterases were present, CYP450was the major pathway Other halogenated esters were tested such ascompounds in which R is CH(CH₂F)₂, C(CH₃)(CF₃)₂, polyfluorinatedcyclohexyl. In every case the metabolism was mainly by esterase.

In a separate set of incubations the effects of paraoxon, a knownesterase inhibitor, were tested in order to confirm that the metabolismobserved was due to esterase. Paraoxon, at a final concentration of 320μg/mL, effectively inhibited the metabolism of the halogenated esters,as is shown in FIG. 15, confirming that esterase was the primary enzymeinvolved in the metabolism of halogenated compounds.

Further data generated essentially using the assay protocol describedabove appears below.

Stability of Several Compounds (at 2 μM Final Concentration) in PooledHuman Microsomes

CYP + Esterase Esterase Buffer VKER % Stability at % Stability %Stability IC₅₀ 90 min at 90 min at 90 min Structure (μM) (Est T^(1/2) )(Est T^(1/2)) (Est T^(1/2))

>30.00 101% (>90 min) ND 99% (>90 min)

3.38 69%** (>90 min) 70%** (>90 min) 108%** (>90 min)

5.07 91%** (>90 min) 96%** (>90 min) 92%** (>90 min)

4.02 70% (>90 min) 86% (>90 min) 123% (>90 min)

4.15 24% (~30 min) 27% (~30 min) 113% (>90 min) Warfarin 3.0 ± 0.8* *isthe average of 3 experiments conducted on 3 separate days

The results indicate that incorporation of an ester bond makes itpossible to shift metabolism from CYP-mediated degradation tocarboxylesterase-mediated pathways.

EXAMPLE 11 HEK-293 Cell Study

Electrophysiological recordings of I_(Kr) in stably transfected HEK-293cells were made in the whole cell configuration of the patch-clamptechnique (Hamill et al, 1981) using an Axopatch 200B amplifier (AxonInstruments, Foster City, Calif.). Patch microelectrodes were pulledfrom 1.5-mm borosilicate glass tubing using a two-stage vertical pipettepuller (Narishige, East Meadow, N.Y.). When filled with recordingsolution, patch microelectrodes had a resistance of 3-5 MΩ. HEK-293cells were plated in 35 mm plastic cell and tissue culture dishes for2-3 days. For application of drug-containing solutions to cells, theSF-77B system (Warner Instrument Corp, Hamden, Conn.) was used. Solutionexchanges were completed within 20 ms. Current data were digitizedonline using a DigiData 1200A analog-to-digital board (Axon Instruments)and stored on the hard disc of an IBM compatible Pentium computer(GP7-600 MHz, Gateway Computer, Sioux City, N.D.). Voltage-clampexperimental protocols and off-line data analysis were performed usingthe software program pCLAMP7 (Axon Instruments). The experiments wereperformed at room temperature (22-23° C.).

The composition of the extracellular control solution is described inthe table below. Its pH was adjusted to 7.4 using NaOH.

The solution for filling the patch electrodes is described in the tablebelow and its pH was adjusted to 7.4 using KOH.

Electrophysiological recordings of I_(Kr) Source mammalian HEK-293 cellsexpressing the hERG gene Potential −80 mV Depolarization +10 mV for 20 sRepolarization −50 mM for 5 s Incubation 22-23° C. TemperatureExtracellular NaCl 140 mM, KCl 4 mM, CaCl₂ 2 mM, MgCl₂ 1 mM, solution4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) 10 mM, andglucose 11 mM Electrode Potassium gluconate 135 mM, MgCl₂ 1 mM, Bufferethyleneglycoltetraacetic acid (EGTA) 5 mM, HEPES 10 mM, MgATP 5 mM

The effect of warfarin,2,2,2-trifluoro-1-methyl-1-(trifluoromethyl)ethyl4-[(4-hydroxy-2-oxo-2H-chromen-3-yl)methyl]benzoate and itscorresponding acid metabolite,4-[(4-hydroxy-2-oxo-2H-chromen-3-yl)methyl]benzoic acid on I_(Kr) wasstudied in a stably transfected HEK-293 cell line using a two-pulseprotocol. Cells were clamped at a holding potential of −80 mV anddepolarized to +10 mV for a 20 s period to activate I_(Kr) and then arepolarizing step to −50 mV was applied for 5 sec to elicit an outwarddeactivating tail current (tail I_(Kr)). The two-pulse protocol wasapplied every 45 s. Tail I_(Kr) amplitude was measured as the differencebetween the peak current and baseline current at −50 mV in control andin the presence of ATI-compounds when steady-state block was obtained.

The study showed that 2,2,2-trifluoro-1-methyl-1-(trifluoromethyl)ethyl4-[(4-hydroxy-2-oxo-2H-chormen-3-yl)methyl]benzoate and itscorresponding acid metabolite,4-[(4-hydroxy-2-oxo-2H-chromen-3-yl)methyl]benzoic acid, had noinhibitory effect on human I_(Kr) (IC₅₀>100 and >1000 μM, respectively.)Nor did either compound exhibit significant activity in a broad cellularand biochemical receptor screening assay, at concentrations up to 10 μM.

Modifications of the compounds disclosed herein can readily be made bythose skilled in the art. Thus, analogs, derivatives, enantiomers andsalts of the exemplified compounds are within the scope of the subjectinvention. With knowledge of the compounds of the subject invention, andtheir structures, skilled chemists can use known procedures tosynthesize these compounds from available substrates.

All patents, patent applications, provisional applications, andpublications referred to or cited herein are incorporated by referencein their entirety, including all figures and tables, to the extent theyare not inconsistent with the explicit teachings of this specification.

It should be understood that the examples and embodiments describedherein are for illustrative purposes only and that various modificationsor changes in light thereof will be suggested to persons skilled in theart and are to be included within the spirit and purview of thisapplication.

The invention and the manner and process of making and using it, are nowdescribed in such full, clear, concise and exact terms as to enable anyperson skilled in the art to which it pertains, to make and use thesame. It is to be understood that the foregoing describes preferredembodiments of the invention and that modifications may be made thereinwithout departing from the spirit or scope of the invention as set forthin the claims To particularly point out and distinctly claim the subjectmatter regarded as invention, the following claims conclude thisspecification.

1. A method of treating a coagulation disorder comprising administeringto a patient in need of anticoagulation therapy an effective amount of acomposition comprising a compound according to Formula VI:

or pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier, diluent, or excipient wherein R is C₁-C₈ alkylsubstituted with at least one halogen, wherein said halogen is fluoro.2. A method according to claim 1, wherein R is C₃-C₇ alkyl substitutedwith at least one halogen, wherein said halogen is fluoro.
 3. A methodaccording to claim 1, wherein R is C₃-C₆ alkyl substituted with at leastone halogen, wherein said halogen is fluoro.
 4. A method according toclaim 1, wherein R is C₃-C₆ alkyl substituted with at least twohalogens, wherein each said halogen is fluoro.
 5. A method according toclaim 1, wherein R is C₃-C₆ alkyl substituted with at least sixhalogens, wherein each said halogen is fluoro.
 6. A method according toclaim 1, wherein R is


7. A method according to claim 1, wherein the compound is1,1,1,3,3,3-hexafluoro-2-methylpropan-2-yl4-((4-hydroxy-2-oxo-2H-chromen-3-yl)methyl)benzoate, or pharmaceuticallyacceptable salts thereof.
 8. A method according to claim 1, wherein thecoagulation disorder is selected from the group consisting of venousthrombosis, pulmonary embolism, thromboembolic complications associatedwith atrial fibrillation, and thromboembolic complications associatedwith cardiac valve replacement.
 9. A method according to claim 6,wherein the coagulation disorder is selected from the group consistingof venous thrombosis, pulmonary embolism, thromboembolic complicationsassociated with atrial fibrillation, and thromboembolic complicationsassociated with cardiac valve replacement.
 10. A method of inhibitingvitamin K epoxide reductase comprising administering to an individual aneffective amount of a composition comprising a compound according toFormula VI:

or pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier, diluent, or excipient wherein R is C₁-C₈ alkylsubstituted with at least one halogen, wherein said halogen is fluoro.11. A method according to claim 10, wherein R is C₃-C₇ substituted withat least one halogen, wherein said halogen is fluoro.
 12. A methodaccording to claim 10, wherein R is C₃-C₆ alkyl substituted with atleast one halogen, wherein said halogen is fluoro.
 13. A methodaccording to claim 10, wherein R is C₃-C₆ alkyl substituted with atleast two halogens, wherein each said halogen is fluoro.
 14. A methodaccording to claim 10, wherein R is C₃-C₆ alkyl substituted with atleast six halogens, wherein each said halogen is fluoro.
 15. A methodaccording to claim 10, wherein R is


16. A method according to claim 10, wherein the compound according toFormula VI is 1,1,1,3,3,3-hexafluoro-2-methylpropan-2-yl4-((4-hydroxy-2-oxo-2H-chromen-3-yl)methyl)benzoate, or pharmaceuticallyacceptable salts thereof.
 17. A method of inhibiting clotting factorsynthesis comprising administering to an individual an effective amountof a composition comprising a compound according to Formula VI:

or pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier, diluent, or excipient wherein R is C₁-C₈ alkylsubstituted with at least one halogen, wherein said halogen is fluoro.18. A method according to claim 17, wherein R is C₃-C₇ alkyl substitutedwith at least one halogen, wherein said halogen is fluoro.
 19. A methodaccording to claim 17, wherein R is C₃-C₆ alkyl substituted with atleast one halogen, wherein each said halogen is fluoro.
 20. A methodaccording to claim 17, wherein R is C₃-C₆ alkyl substituted with atleast two halogens, wherein each said halogen is fluoro.
 21. A methodaccording to claim 17, wherein R is C₃-C₆ alkyl substituted with atleast six halogens, wherein each said halogen is fluoro.
 22. A methodaccording to claim 17, wherein R is


23. A method according to claim 17, wherein the compound according toFormula VI is 1,1,1,3,3,3-hexafluoro-2-methylpropan-2-yl4-((4-hydroxy-2-oxo-2H-chromen-3-yl)methyl)benzoate, or pharmaceuticallyacceptable salts thereof.
 24. A method according to claim 17, whereinthe clotting factors are one or more of Factor II, Factor VI, Factor IX,Factor X, protein C and protein S.
 25. A method according to claim 23,wherein the clotting factors are one or more of Factor II, Factor VII,Factor IX, Factor X, protein C and protein S.